Barbituric acid derivatives as inhibitors of TNF-α converting enzyme (TACE) and/or matrix metalloproteinases

ABSTRACT

The present application describes novel barbituric acid derivatives of formula I: 
                         
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, L, R 1 , R 2 , R 3 , R 4 , R 5 , n, W, U, X, Y, Z, U a , X a , Y a , and Z a  are defined in the present specification, which are useful as TNF-α converting enzyme (TACE) and matrix metalloproteinases (MMP) inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. ProvisionalApplication No. 60/342,658, filed Dec. 20, 2001, the disclosure of whichis incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates generally to novel barbituric acid derivatives asinhibitors of TNF-α converting enzyme (TACE), matrix metalloproteinases(MMP), aggrecanse or a combination thereof, pharmaceutical compositionscontaining the same, and methods of using the same.

BACKGROUND OF THE INVENTION

There is now a body of evidence that metalloproteases (MP) are importantin the uncontrolled breakdown of connective tissue, includingproteoglycan and collagen, leading to resorption of the extracellularmatrix. This is a feature of many pathological conditions, such asrheumatoid and osteoarthritis; corneal, epidermal, or gastriculceration; tumor metastasis or invasion; periodontal disease; and bonedisease. Normally these catabolic enzymes are tightly regulated at thelevel of their synthesis as well as at their level of extracellularactivity through the action of specific inhibitors, such asalpha-2-macroglobulins and TIMPs (tissue inhibitors of metalloprotease),which form inactive complexes with the MP's.

Osteo- and rheumatoid arthritis (OA and RA respectively) are destructivediseases of articular cartilage characterized by localized erosion ofthe cartilage surface. Findings have shown that articular cartilage fromthe femoral heads of patients with OA, for example, had a reducedincorporation of radiolabeled sulfate over controls, suggesting thatthere must be an enhanced rate of cartilage degradation in OA (Mankin etal. J. Bone Joint Surg. 1970, 52A, 424–434). There are four classes ofprotein degradative enzymes in mammalian cells: serine, cysteine,aspartic, and metalloprotease. The available evidence supports that itis the metalloproteases that are responsible for the degradation of theextracellular matrix of articular cartilage in OA and RA. Increasedactivities of collagenases and stromelysin have been found in OAcartilage and the activity correlates with the severity of the lesion(Mankin et al. Arthritis Rheum. 1978, 21, 761–766, Woessner et al.Arthritis Rheum. 1983, 26, 63–68, and Woessner et al. Arthritis Rheum.1984, 27, 305–312). In addition, aggrecanase has been identified asproviding the specific cleavage product of proteoglycan found in RA andOA patients (Lohmander L. S. et al. Arthritis Rheum. 1993, 36, 1214–22).

Therefore, metalloproteases (MP) have been implicated as the key enzymesin the destruction of mammalian cartilage and bone. It can be expectedthat the pathogenesis of such diseases can be modified in a beneficialmanner by the administration of MP inhibitors, and many compounds havebeen suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem.1990, 25, 175–184, AP, San Diego).

Tumor necrosis factor-α (TNF-α) is a cell-associated cytokine that isprocessed from a 26 kd precursor form to a 17 kd soluble form. TNF-α hasbeen shown to be a primary mediator in humans and in animals ofinflammation, fever, and acute phase responses, similar to thoseobserved during acute infection and shock. Excess TNF-α has been shownto be lethal. There is now considerable evidence that blocking theeffects of TNF-α with specific antibodies can be beneficial in a varietyof circumstances including autoimmune diseases such as RA (Feldman etal, Lancet 1994, 344, 1105), non-insulin dependent diabetes melitus(Lohmander, L. S. et al. Arthritis Rheum. 1993, 36, 1214–22), andCrohn's disease (MacDonald et al. Clin. Exp. Immunol. 1990, 81, 301).

Compounds which inhibit the production of TNF-α are therefore oftherapeutic importance for the treatment of inflammatory disorders. Thisinvention describes molecules that inhibit TNF-α converting enzyme(TACE) and hence the secretion of active TNF-α from cells. These novelmolecules provide a means of mechanism based therapeutic interventionfor diseases including but not restricted to septic shock, haemodynamicshock, sepsis syndrome, post ischemic reperfusion injury, malaria,Crohn's disease, inflammatory bowel diseases, mycobacterial infection,meningitis, psoriasis, congestive heart failure, fibrotic diseases,cachexia, graft rejection, cancer, diseases involving angiogenesis,autoimmune diseases, skin inflammatory diseases, OA, RA, multiplesclerosis, radiation damage, hyperoxic alveolar injury, periodontaldisease, HIV, and non-insulin dependent diabetes melitus.

Since excessive TNF-α production has been noted in several diseaseconditions also characterized by MMP-mediated tissue degradation,compounds which inhibit both MMPs and TNF-α production may also have aparticular advantage in diseases where both mechanisms are involved.

It is desirable to find new compounds with improved pharmacologicalcharacteristics compared with known MMP and/or TACE inhibitors. Forexample, it is preferred to find new compounds with improved MMP and/orTACE inhibitory activity and selectivity for an MMP and/or TACE versusother metalloproteases (e.g., specificity for one MMP versus another).It is also desirable and preferable to find compounds with advantageousand improved characteristics in one or more of the following categories:(a) pharmaceutical properties (e.g., solubility, permeability, andamenability to sustained release formulations); (b) dosage requirements(e.g., lower dosages and/or once-daily dosing); (c) factors whichdecrease blood concentration peak-to-trough characteristics (e.g.,clearance and/or volume of distribution); (d) factors that increase theconcentration of active drug at the receptor (e.g., protein binding andvolume of distribution); (e) factors that decrease the liability forclinical drug-drug interactions (e.g., cytochrome P450 enzyme inhibitionor induction); (f) factors that decrease the potential for adverseside-effects (e.g., pharmacological selectivity beyond serine proteases,potential chemical or metabolic reactivity, and limited CNSpenetration); and (g) factors that improve manufacturing costs orfeasibility (e.g., difficulty of synthesis, number of chiral centers,chemical stability, and ease of handling).

The compounds of the present invention act as inhibitors of MPs, inparticular TACE, MMPs, and/or aggrecanase. These novel molecules areprovided as anti-inflammatory compounds and cartilage protectingtherapeutics.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel barbituric acidderivatives useful as MMP, TACE, and/or aggrecanase inhibitors orpharmaceutically acceptable salts or prodrugs thereof.

The present invention provides pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating inflammatorydisorders, comprising: administering to a mammal, in need of suchtreatment, a therapeutically effective amount of at least one of thecompounds of the present invention or a pharmaceutically acceptable saltor prodrug form thereof.

The present invention provides a method of treating a condition ordisease mediated by MMPS, TACE, aggrecanase, or a combination thereof ina mammal, comprising: administering to the mammal in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

The present invention provides a method comprising: administering acompound of the present invention or a pharmaceutically acceptable saltor prodrug form thereof in an amount effective to treat a condition ordisease mediated by MMPS, TACE, aggrecanase, or a combination thereof.

The present invention provides novel compounds of the present inventionfor use in therapy.

The present invention provides the use of novel compounds of the presentinvention for the manufacture of a medicament for the treatment of acondition or disease mediated by MMPs, TACE, aggrecanase, or acombination thereof.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formula I:

or pharmaceutically acceptable salt or prodrug forms thereof, wherein A,B, L, R¹, R², R³, R⁴, R⁵, n, W, U, X, Y, Z, U^(a), X^(a), Y^(a), andZ^(a) are defined below, are effective TACE and matrix metalloproteinsesinhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in an embodiment, the present invention provides a novelcompound of formula I:

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein;

-   A is C(═O), C(═S) or CH₂;-   B is O or S;-   L is O or S;-   W is selected from (CR^(a)R^(a1))_(m), C₂₋₃ alkenylene, and C₂₋₃    alkynylene;-   U is selected from: C(O), CR^(a)(OH), C(O)O, OC(O), C(O)NR^(a1),    NR^(a1)C(O), OC(O)O, OC(O)NR^(a1), NR^(a1)C(O)O, and    NR^(a1)C(O)NR^(a1);-   X is absent or is selected from C₁₋₃ alkylene, C₂₋₃ alkenylene, and    C₂₋₃ alkynylene;-   Y is absent or is selected from O, NR^(a1), S(O)_(p), and C(O);-   Z is selected from a C₃₋₁₃ carbocycle substituted with 0–5 R^(b),    and a 5–14 membered heterocycle comprising carbon atoms and 1–4    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–5 R^(b);-   U^(a) is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH),    C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O, OC(O)NR^(a1),    NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1),    NR^(a1)S(O)_(p), and NR^(a1)SO₂NR^(a1);-   X^(a) is absent or is selected from C₁₋₁₀ alkylene, C₂₋₁₀    alkenylene, and C₂₋₁₀ alkynylene;-   Y^(a) is absent or is selected from O, NR^(a1), S(O)_(p), and C(O);-   Z^(a) is selected from a C₃₋₁₃ carbocycle substituted with 0–5 R^(c)    and a 5–14 membered heterocycle comprising carbon atoms and 1–4    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–5 R^(c);-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   R¹ is selected from CHF₂, CH₂F, CF₃, C₁₋₆ alkylene-Q, C₂₋₆    alkenylene-Q, C₂₋₆ alkynylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)OC(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)OC(O)OR^(a1),    (CR^(a)R^(a1))_(r1)OC(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(s)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)SO₂NR^(a)R^(a1), a C₃₋₁₃ carbocycle    substituted with 0–5 R^(d), and a 5–14 membered heterocycle    comprising carbon atoms and 1–4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0–5 R^(d);-   R² is selected from Q¹, C₁₋₆ alkylene-Q¹, C₂₋₆ alkenylene-Q¹, C₂₋₆    alkynylene-Q¹, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(r1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q¹, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   R³ is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆    alkynylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)OC(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)OC(O)OR^(a1), (CR^(a)R^(a1))_(r1)OC(O)    NR^(a)R^(a1), (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q, and    (CR^(a)R^(a1))_(r1)NR^(a)SO₂NR^(a)R^(a1);-   Q, at each occurrence, is independently selected from H, CHF₂, CH₂F,    CF₃, a C₃₋₁₃ carbocycle substituted with 0–5 R^(d), and a 5–14    membered heterocycle comprising carbon atoms and 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    substituted with 0–5 R^(d);-   Q¹, at each occurrence, is independently selected from H, a C₃₋₁₃    carbocycle substituted with 0–5 R^(d), and a 5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–5 R^(d);-   R⁴ is selected from H, C₁₋₆ alkyl substituted with 0–1 R^(b), C₂₋₆    alkenyl substituted with 0–1 R^(b), and C₂₋₆ alkynyl substituted    with 0–1 R^(b);-   R⁵ is selected from H, C₁₋₆ alkyl substituted with 0–1 R^(b), C₂₋₆    alkenyl substituted with 0–1 R^(b), and C₂₋₆ alkynyl substituted    with 0–1 R^(b);-   n is 0 or 1;-   alternatively, R² and R³, together with the carbon atom to which    they are attached, combine to form a 3–8 membered carbocyclic or    heterocyclic ring comprising carbon atoms, 0–2 ring heteroatoms    selected from O, N, NR¹⁰, and S(O)_(p), and 0–2 double bonds, and    substituted with 0–3 R^(c); and the carbocyclic or heterocyclic ring    is optionally fused to a 5–6 membered carbocycle substituted with    0–3 R^(c) or a 5–6 membered heterocycle consisting of carbon atoms    and 1–3 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–3 R^(c);-   alternatively, when n is 1, R² and R⁴, together with the carbon    atoms to which they are attached, combine to form a 3–8 membered    carbocyclic or heterocyclic ring comprising carbon atoms, 0–2 ring    heteroatoms selected from O, N, NR¹⁰, and S(O)_(p), and 0–2 double    bonds, and substituted with 0–3 R^(c); and the carbocyclic or    heterocyclic ring is optionally fused to a 5–6 membered carbocycle    substituted with 0–3 R^(c) or a 5–6 membered heterocycle consisting    of carbon atoms and 1–3 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0–3 R^(c);-   alternatively, when n is 1, R⁴ and R⁵, together with the carbon atom    to which they are attached, combine to form a 3–8 membered    carbocyclic or heterocyclic ring comprising carbon atoms, 0–2 ring    heteroatoms selected from O, N, NR¹⁰, and S(O)_(p), and 0–2 double    bonds, and substituted with 0–3 R^(c); and the carbocyclic or    heterocyclic ring is optionally fused to a 5–6 membered carbocycle    substituted with 0–3 R^(c) or a 5–6 membered heterocycle consisting    of carbon atoms and 1–3 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0–3 R^(c);-   R¹⁰, at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–2 R^(c1), C₂₋₆ alkenyl substituted with 0–2    R^(c1), C₂₋₆ alkynyl substituted with 0–2 R^(c1),    (CR^(a)R^(a1))_(s)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)OH,    (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)C(S)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(S)NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)OC(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(s)NR^(a)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)SO₂R^(a3),    (CR^(a)R^(a1))_(s)NR^(a)SO₂NR^(a)R^(a1), (CR^(a)R^(a1))_(r)—C₃₋₁₀    carbocycle substituted with 0–2 R^(c1), and (CR^(a)R^(a1))_(r)-5–14    membered heterocycle consisting of carbon atoms and 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    substituted with 0–2 R^(c1);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, and benzyl;-   R^(a1), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–1 R^(e), C₂₋₆ alkenyl substituted with 0–1    R^(e), C₂₋₆ alkynyl substituted with 0–1 R^(e), and —(CH₂)_(r)-3–8    membered carbocyclic or heterocyclic ring comprising carbon atoms    and 0–2 ring heteroatoms selected from N, NR^(a2), O, and S(O)_(p),    and substituted with 0–3 R^(e);-   alternatively, R^(a) and R^(a1), when attached to a nitrogen, are    taken together with the nitrogen to which they are attached, form a    5 or 6 membered heterocycle comprising carbon atoms and 0–1    additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p);-   R^(a2), at each occurrence, is independently selected from C₁₋₄    alkyl, phenyl, and benzyl;-   R^(a3) ₁ at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–1 R^(c1), C₂₋₆ alkenyl substituted with 0–1    R^(c1), C₂₋₆ alkynyl substituted with 0–1 R^(c1), and —(CH₂)_(r)-3–8    membered carbocyclic or heterocyclic ring comprising carbon atoms    and 0–2 ring heteroatoms selected from N, NR^(a2), O, and S(O)_(p),    and substituted with 0–3 R^(c1);-   R^(b), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0–1 R^(c1), OR^(a), SR^(a), Cl, F, Br, I, ═O, —CN,    NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),    C(S)NR^(a)R^(a1), NR^(a)C(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1),    NR^(a)C(O)OR^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),    NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),    S(O)_(p)R^(a3), CF₃, CF₂CF₃, CHF₂, CH₂F, and phenyl;-   R^(c), at each occurrence, is independently selected from H, OR^(a),    Cl, F, Br, I, ═O, —CN, NO₂, CF₃, CF₂CF₃, CH₂F, CHF₂,    (CR^(a)R^(a1))_(r)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)C(═NCN)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)C(═NR^(a))NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)C(═NOR^(a))NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)OH, (CR^(a)R^(a1))_(r1)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(S)OR^(a1),    (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(S)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)OC(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3),    (CR^(a)R^(a1))_(r)NR^(a)SO₂NR^(a)R^(a1); C₁₋₆ alkyl substituted with    0–2 R^(c1); C₂₋₆ alkenyl substituted with 0–2 R^(c1); C₂₋₆ alkynyl    substituted with 0–2 R^(c1); (CR^(a)R^(a1))_(r)—C₃₋₁₀ carbocycle    substituted with 0–2 R^(c1); and (CR^(a)R^(a1))_(r)-5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–2 R^(c1);-   alternatively, when two R^(c) groups are attached to the same carbon    atom, they form a spiro ring C that is a 3–11 membered carbocycle or    heterocycle substituted with 0–2 R^(c1) and comprising: carbon    atoms, 0–4 ring heteroatoms selected from O, N, and S(O)_(p), and    0–2 double bonds, provided that ring C contains other than a S—S,    O—O, or S—O bond;-   alternatively, when two R^(c) groups are attached to adjacent carbon    atoms, together with the carbon atoms to which they are attached    they form a 5–7 membered carbocyclic or heterocyclic ring D    substituted with 0–2 R^(c1) and consisting of carbon atoms, 0–2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and 0–3 double bonds;-   R^(c1), at each occurrence, is independently selected from H, C₁₋₆    alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a),    C(O)OR^(a), C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1),    OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, OCF₃, CF₂CF₃, CH₂F, and    CHF₂;-   R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0–2 R^(e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl,    F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a),    C(O)NR^(a)R^(a1), C(S)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1),    OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a3), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, CF₂CF₃, (CH₂)_(r)—C₃₋₁₀    carbocycle substituted with 0–2 R^(e), and a (CH₂)_(r)-5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–2 R^(e);-   R^(e), at each occurrence, is independently selected from H, C₁₋₆    alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a), C(O)R^(a),    C(O)OR^(a), C(O)NR^(a)R^(a), R^(a)NC(O)NR^(a)R^(a),    OC(O)NR^(a)R^(a), R^(a)NC(O)OR^(a), S(O)₂NR^(a)R^(a),    NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a), OS(O)₂NR^(a)R^(a),    NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, OCF₃, CF₂CF₃, CH₂F, and    CHF₂;-   m, at each occurrence, is selected from 0, 1, 2 and 3;-   p, at each occurrence, is selected from 0, 1, and 2;-   r, at each occurrence, is selected from 0, 1, 2, 3, and 4;-   r1, at each occurrence, is selected from 0, 1, 2, 3, and 4;-   s, at each occurrence, is selected from 2, 3, and 4; and-   provided that when A is C(═O), L is O, R¹ is phenyl, U is NHC(O),    and Z is 2-oxo-chromen-3-yl, then Z^(a) is other than    2-hydroxymethyl-3,4,5-trihydroxy-tetrahydopyran.    [2] In another embodiment, the present invention provides a novel    compound, wherein;-   W is (CHR^(a))_(m) or C₂₋₃ alkenylene;-   U is selected from: C(O), C(O)O, OC(O), C(O)NR^(a1), and    NR^(a1)C(O);-   X is absent or is C₁₋₃ alkylene;-   U^(a) is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH),    C(O)O, C(O)NR^(a1), NR^(a1)C(O), S(O)_(p), S(O)_(p)NR^(a1), and    NR^(a1)S(O)_(p);-   X^(a) is absent or is selected from C₁₋₄ alkylene, C₂₋₄ alkenylene,    and C₂₋₄ alkynylene;-   Y^(a) is absent or is selected from O and NR^(a1);-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   R¹ is selected from CHF₂, CH₂F, CF₃, C₁₋₆ alkylene-Q, C₂₋₆    alkenylene-Q, C₂₋₆ alkynylene-Q,    (CR^(a)R^(a1))_(r1)OR^(a1)(CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q, a C₃₋₁₀ carbocycle    substituted with 0–5 R^(d), and a 5–10 membered heterocycle    comprising carbon atoms and 1–4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0–5 R^(d);-   R² is selected from Q¹, C₁₋₆ alkylene-Q¹, C₂₋₆ alkenylene-Q¹, C₂₋₆    alkynylene-Q¹, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q¹, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   R³ is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆    alkynylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1), and    (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q;-   Q, at each occurrence, is independently selected from H, CF₃, a    C₃₋₁₃ carbocycle substituted with 0–5 R^(d), and a 5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–5 R^(d);-   Q¹, at each occurrence, is independently selected from H, a C₃₋₁₀    carbocycle substituted with 0–5 R^(d), and a 5–10 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–5 R^(d);-   R⁴ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;-   R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;-   n is 0 or 1;-   alternatively, R² and R³, together with the carbon atom to which    they are attached, combine to form a 3–8 membered carbocyclic or    heterocyclic ring comprising carbon atoms, 0–2 ring heteroatoms    selected from O, N, NR¹⁰, and S(O)_(p), and 0–2 double bonds, and    substituted with 0–2 R^(c);-   alternatively, when n is 1, R² and R⁴, together with the carbon    atoms to which they are attached, combine to form a 3–8 membered    carbocyclic or heterocyclic ring comprising carbon atoms, 0–2 ring    heteroatoms selected from O, N, NR¹⁰, and S(O)_(p), and 0–2 double    bonds, and substituted with 0–2 R^(c);-   alternatively, when n is 1, R⁴ and R⁵, together with the carbon atom    to which they are attached, combine to form a 3–8 membered    carbocyclic or heterocyclic ring comprising carbon atoms, 0–2 ring    heteroatoms selected from O, N, NR¹⁰, and S(O)_(p), and 0–2 double    bonds, and substituted with 0–2 R^(c);-   R¹⁰, at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–2 R^(c1), C₂₋₆ alkenyl substituted with 0–2    R^(c1), C₂₋₆ alkynyl substituted with 0–2 R^(c1),    (CR^(a)R^(a1))_(s)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)SO₂R^(a3), (CR^(a)R^(a1))_(r)—C₃₋₁₀    carbocycle substituted with 0–2 R^(c1), and (CR^(a)R^(a1))_(r)-5–14    membered heterocycle consisting of carbon atoms and 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    substituted with 0–2 R^(c1);-   R^(c), at each occurrence, is independently selected from H, OR^(a),    Cl, F, Br, ═O, —CN, NO₂, NR^(a)R^(a1), CF₃,    (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₁₋₆ alkyl substituted with 0–1    R^(c1); C₂₋₆ alkenyl substituted with 0–1 R^(c1); C₂₋₆ alkynyl    substituted with 0–1 R^(c1); (CH₂)_(r)—C₃₋₆ carbocycle substituted    with 0–2 R^(c1); and (CH₂)_(r)-5–6 membered heterocycle comprising    carbon atoms and 1–4 heteroatoms selected from the group consisting    of N, O, and S(O)_(p), and substituted with 0–2 R^(c1);-   alternatively, when two R^(c) groups are attached to the same carbon    atom, they form a spiro ring C that is a 3–8 membered carbocycle or    heterocycle substituted with 0–2 R^(c1) and comprising: carbon    atoms, 0–4 ring heteroatoms selected from O, N, and S(O)_(p), and    0–2 double bonds, provided that ring C contains other than a S—S,    O—O, or S—O bond; and-   alternatively, when two R^(c) groups are attached to adjacent carbon    atoms, together with the carbon atoms to which they are attached    they form a 5–7 membered carbocyclic or heterocyclic ring D    substituted with 0–2 R^(c1) and consisting of carbon atoms, 0–2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and 0–3 double bonds.    [3] In another embodiment, the present invention provides a novel    compound, wherein;-   A is C(═O) or CH₂;-   B is O;-   L is O;-   U is selected from: C(O), C(O)NR^(a1), and NR^(a1)C(O);-   X is absent, methylene or ethylene;-   Z is selected from:    -   a C₃₋₈ cycloalkyl substituted with 0–5 R^(b);    -   a C₃₋₈ cycloalkenyl substituted with 0–5 R^(b);    -   phenyl substituted with 0–5 R^(b);    -   naphthyl substituted with 0–5 R^(b); and    -   a 5–14 membered heterocycle comprising carbon atoms and 1–4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p), and substituted with 0–5 R^(b);-   U^(a) is absent or is selected from: O, NR^(a1), C(O), C(O)NR^(a1),    NR^(a1)C(O), and S(O)_(p);-   Z^(a) is selected from a C₅₋₁₀ carbocycle substituted with 0–5    R^(c), and a 5–14 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–5 R^(c);-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   R² is selected from Q¹, C₁₋₆ alkylene-Q¹, C₂₋₆ alkenylene-Q¹,    (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q¹, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   Q¹, at each occurrence, is independently selected from H, a C₃₋₆    carbocycle substituted with 0–3 R^(d), and a 5–10 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–3 R^(d);-   R³ is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆    alkynylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   Q, at each occurrence, is independently selected from H, a C₃₋₁₀    carbocycle substituted with 0–3 R^(d), and a 5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–3 R^(d);-   R⁴ is selected from H and C₁₋₆ alkyl;-   R⁵ is selected from H and C₁₋₆ alkyl;-   n is 0 or 1;-   R¹⁰, at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–1 R^(c1), C₂₋₆ alkenyl substituted with 0–1    R^(c1), C₂₋₆ alkynyl substituted with 0–1 R^(c1),    (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)—C₃₋₆ carbocycle substituted with 0–2 R^(c1), and    (CR^(a)R^(a1))_(r)-5–10 membered heterocycle consisting of carbon    atoms and 1–4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), and substituted with 0–2 R^(c1);-   R^(a), at each occurrence, is independently selected from H and C₁₋₆    alkyl;-   R^(a1), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl;-   alternatively, R^(a) and R^(a1), when attached to a nitrogen, are    taken together with the nitrogen to which they are attached, form a    5 or 6 membered heterocycle comprising carbon atoms and 0–1    additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p);-   R^(a3), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, and —(CH₂)_(r)-3–8 membered carbocyclic or    heterocyclic ring comprising carbon atoms and 0–2 ring heteroatoms    selected from N, NR^(a2), O, and S(O)_(p), and substituted with 0–3    R^(c1);-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₃₋₆ carbocycle substituted with    0–2 R^(c1); and 5–6 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(c1);-   alternatively, when two R^(c) groups are attached to the same carbon    atom, they form a spiro ring C that is a 3–8 membered carbocycle or    heterocycle substituted with 0–2 R^(c1) and comprising: carbon    atoms, 0–4 ring heteroatoms selected from O, N, and S(O)_(p), and    0–2 double bonds, provided that ring C contains other than a S—S,    O—O, or S—O bond;-   alternatively, when two R^(c) groups are attached to adjacent carbon    atoms, together with the carbon atoms to which they are attached    they form a 5–6 membered carbocyclic or heterocyclic ring D    substituted with 0–2 R^(c1) and consisting of carbon atoms, 0–2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and 0–3 double bonds;-   R^(c1), at each occurrence, is independently selected from H, C₁₋₄    alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂, C(O)OR^(a), and    C(O)NR^(a)R^(a1);-   R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0–2 R^(e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl,    F, Br, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a),    C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),    S(O)_(p)R^(a3), CF₃, (CH₂)_(r)—C₃₋₆ carbocycle substituted with 0–2    R^(e), and a 5–6 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p); and-   R^(e), at each occurrence, is independently selected from H, C₁₋₄    alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂, C(O)OR^(a), and    C(O)NR^(a)R^(a).    [4] In another embodiment, the present invention provides a novel    compound, wherein;-   W is (CH₂)_(m) or C₂₋₃ alkenylene;-   Z is selected from:    -   a C₄₋₈ cycloalkyl substituted with 0–3 R^(b);    -   a C₄₋₈ cycloalkenyl substituted with 0–3 R^(b);    -   phenyl substituted with 0–3 R^(b);    -   naphthyl substituted with 0–3 R^(b);    -   a 5–10 membered heterocycle substituted with 0–3 R^(b) and        selected from the group: furanyl, tetrahydrofuranyl, thiazolyl,        oxazolyl, imidazolyl, isothiazolyl, isoxazolyl,        4,5-dihydro-isoxazolyl, thiophenyl, triazinyl, pyridyl,        pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl,        pyrazolyl, pyridoimidazole, pyrrolidinyl, pyrrolinyl, indolyl,        indolinyl, benzimidazolyl, benzothiazinyl, benzofuranyl,        benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,        benzisoxazolyl, benzisothiazolyl,quinolinyl,        tetrahydroquinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl,        indazolyl, isobenzofuranyl, isoindazolyl, isoindolinyl,        isoindolyl, isoquinolinyl, methylenedioxyphenyl, quinazolinyl,        thiadiazinyl, and        1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl;-   Z^(a) is selected from:    -   phenyl substituted with 0–3 R^(c);    -   naphthyl substituted with 0–3 R^(c); and a 5–10 membered        heterocycle substituted with 0–3 R^(c) and selected from the        group: furanyl, tetrahydrofuranyl, thiazolyl, oxazolyl,        imidazolyl, isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl,        thiophenyl, triazinyl, pyridyl, pyrimidinyl, piperazinyl,        piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridoimidazole,        pyrrolidinyl, pyrrolinyl, indolyl, indolinyl, benzimidazolyl,        benzothiazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl,        benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl,        quinolinyl, tetrahydroquinolinyl, isoquinolinyl,        tetrahydro-isoquinolinyl, indazolyl, isobenzofuranyl,        isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,        methylenedioxyphenyl, quinazolinyl, thiadiazinyl, and        1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl;-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   R³ is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q,    (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   Q, at each occurrence, is independently selected from H, a C₃₋₆    carbocycle substituted with 0–3 R^(d), and a 5–10 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–3 R^(d);-   R^(a), at each occurrence, is independently selected from H and C₁₋₆    alkyl;-   R^(a1), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl;-   R^(a3), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, and benzyl;-   R^(b), at each occurrence, is independently selected from C₁₋₄    alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),    C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a3), and CF₃;-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₃₋₆ carbocycle substituted with    0–2 R^(c1); and 5–6 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–2 R^(c1); and-   R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0–1 R^(e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl,    F, Br, ═O, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a), C(O)NR^(a)R^(a1),    S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, and    (CH₂)_(r)-phenyl substituted with 0–2 R^(e).    [5] In another embodiment, the present invention provides a novel    compound, wherein;-   X is absent or is methylene;-   Y is absent or is O;-   Z is selected from:    -   phenyl substituted with 0–3 R^(b);    -   naphthyl substituted with 0–3 R^(b);    -   thiophenyl substituted with 0–2 R^(b);    -   oxazolyl substituted with 0–1 R^(b);    -   isoxazolyl substituted with 0–1 R^(b); and    -   thiazolyl substituted with 0–1 R^(b);-   U^(a) is absent or is O;-   X^(a) is selected from CH₂ and CH₂CH₂;-   Y^(a) is absent or is O;-   Z^(a) is selected from:    -   phenyl substituted with 0–3 R^(c);    -   pyridyl substituted with 0–3 R^(c);    -   indolyl substituted with 0–3 R^(c);    -   quinolinyl substituted with 0–3 R^(c);    -   benzimidazolyl substituted with 0–3 R^(c); and    -   1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl substituted        with 0–3 R^(c);-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   R¹ is selected from C₁₋₆ alkylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(s)-Q,    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1),    -   a C₃₋₆ carbocycle substituted with 0–3 R^(d), and a 5–10        membered heterocycle comprising carbon atoms and 1–4 heteroatoms        selected from the group consisting of N, O, and S(O)_(p) and        substituted with 0–3 R^(d);-   R² is selected from Q¹, C₁₋₆ alkylene-Q¹, C(O)NR^(a)R^(a1),    C(O)(CR^(a)R^(a1))_(r)-Q¹, C(O)OR^(a1), and    S(O)_(p)(CR^(a)R^(a1))_(r)-Q¹;-   Q¹, at each occurrence, is independently selected from H, a    cyclopropyl substituted with 0–1 R^(d), cyclopentyl substituted with    0–1 R^(d), cyclohexyl substituted with 0–1 R^(d), phenyl substituted    with 0–2 R^(d), and a heteroaryl substituted with 0–3 R^(d), wherein    the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl,    furanyl, imidazolyl, and isoxazolyl;-   R³ is selected from Q, C₁₋₆ alkylene-Q, (CR^(a)R^(a1))_(r)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(s)—Q, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   R⁴ is selected from H and C₁₋₄ alkyl;-   R⁵ is selected from H and C₁₋₄ alkyl; and-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    and phenyl.    [6] In another embodiment, the present invention provides a novel    compound, wherein;-   R¹ is selected from C₁₋₆ alkylene-Q, NR^(a)(CR^(a)R^(a1))_(r)-Q,    C(O)(CR^(a)R^(a1))_(r)-Q, C(O)OR^(a1), C(O)NR^(a)R^(a1),    NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q, NR^(a)C(O)OR^(a1),    S(O)_(p)(CR^(a)R^(a1))_(r)-Q, SO₂NR^(a)R^(a1), cyclopropyl    substituted with 0–1 R^(d), cyclopentyl substituted with 0–1 R^(d),    cyclohexyl substituted with 0–1 R^(d), phenyl substituted with 0–2    R^(d), and a heterocycle substituted with 0–3 R^(d), wherein the    heterocycle is selected from pyridyl, quinolinyl, thiazolyl,    furanyl, imidazolyl, isoxazolyl, piperindinyl, and piperazinyl;-   R³ is selected from Q, C₁₋₆ alkylene-Q, C(O)(CR^(a)R^(a1))_(r)-Q,    C(O)OR^(a1), C(O)NR^(a)R^(a1), C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q, and    S(O)_(p)(CR^(a)R^(a1))_(r)-Q;-   Q, at each occurrence, is independently selected from H, cyclopropyl    substituted with 0–1 R^(d), cyclopentyl substituted with 0–1 R^(d),    cyclohexyl substituted with 0–1 R^(d), phenyl substituted with 0–2    R^(d), and a heteroaryl substituted with 0–3 R^(d), wherein the    heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl,    imidazolyl, and isoxazolyl;-   R⁴ is selected from H, methyl, and ethyl;-   R⁵ is selected from H, methyl, and ethyl;-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    and (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3); and-   r, at each occurrence, is selected from 0, 1, 2, and 3.    [7] In another preferred embodiment, the present invention provides    a novel compound selected from the group:-   5-methyl-5-(3-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-3-oxopropyl)-2,4,6(1H,3H,5H)-pyrimidinetrione;-   4-[(2-methyl-4-quinolinyl)methoxy]-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]benzamide;-   4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]benzamide;-   4-[(2-methyl-4-quinolinyl)methyl]-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]benzamide;-   4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]benzamide;-   N-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)acetamide;-   tert-butyl    4-{5-[({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)methyl]-2,4,6-trioxohexahydro-5-pyrimidinyl}-1-piperazinecarboxylate;-   4-[(2-methyl-4-quinolinyl)methoxy]-N-{[2,4,6-trioxo-5-(1-piperazinyl)hexahydro-5-pyrimidinyl]methyl}benzamide;-   N-{[5-(4-methyl-1-piperazinyl)-2,4,6-trioxohexahydro-5-pyrimidinyl]methyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;-   4-[(2-methyl-4-quinolinyl)methoxy]-N-({2,4,6-trioxo-5-[4-(2-propynyl)-1-piperazinyl]hexahydro-5-pyrimidinyl}methyl)benzamide;-   4-[(2-methyl-4-quinolinyl)methoxy]-N-({5-[4-(methylsulfonyl)-1-piperazinyl]-2,4,6-trioxohexahydro-5-pyrimidinyl}methyl)benzamide;-   tert-butyl    5-[({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)methyl]-2,4,6-trioxohexahydro-5-pyrimidinylcarbamate;-   N-[(5-methyl-2,4-dioxohexahydro-5-pyrimidinyl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;-   2-(5-methyl-2,4-dioxohexahydro-5-pyrimidinyl)-N-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetamide;-   N-[(5-ethyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;-   N-{[5-(4-benzyl-1-piperazinyl)-2,4,6-trioxohexahydro-5-pyrimidinyl]methyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;-   N-[(5-isopropyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;-   6-[(2-methyl-4-quinolinyl)methoxy]-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]-2-naphthamide;-   N-{[5-(4-isopropyl-1-piperazinyl)-2,4,6-trioxohexahydro-5-pyrimidinyl]methyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;-   N-{[5-(4-acetyl-1-piperazinyl)-2,4,6-trioxohexahydro-5-pyrimidinyl]methyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;-   4-[(2-methyl-4-quinolinyl)methoxy]-N-({2,4,6-trioxo-5-[4-(3-pyridinylcarbonyl)-1-piperazinyl]hexahydro-5-pyrimidinyl}methyl)benzamide;-   N-[(5-benzyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;-   3-(2-methyl-4-quinolinyl)-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]benzamide;-   tert-butyl    4-{5-[({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)methyl]-2,4,6-trioxohexahydro-5-pyrimidinyl}-1-piperidinecarboxylate;-   4-[(2-methyl-4-quinolinyl)methoxy]-N-{[2,4,6-trioxo-5-(4-piperidinyl)hexahydro-5-pyrimidinyl]methyl}benzamide;-   N-({5-[1-(2,2-dimethylpropanoyl)-4-piperidinyl]-2,4,6-trioxohexahydro-5-pyrimidinyl}methyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;-   N-(5-methyl-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl)-4-phenoxy-benzamide;-   biphenyl-4-carboxylic acid    [(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]amide;-   4-[(2-methyl-4-quinolinyl)methoxy]-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)-(4-pyridinyl)methyl]benzamide;-   4-(2-methyl-quinolin-4-ylmethoxy)-N-[2,4,6-trioxo-5-(4-pyridin-3-ylmethyl-piperazin-1-yl)-hexahydro-pyrimidin-5-ylmethyl]-benzamide;-   N-[5-(1-methyl-piperidin-4-yl)-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;-   N-[5-(1-isopropyl-piperidin-4-yl)-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;-   4-(2-methyl-quinolin-4-ylmethoxy)-N-[2,4,6-trioxo-5-(1-prop-2-ynyl-piperidin-4-yl)-hexahydro-pyrimidin-5-ylmethyl]-benzamide;-   N-[5-(1-methanesulfonyl-piperidin-4-yl)-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;-   4-(2-methyl-quinolin-4-ylmethoxy)-N-[2,4,6-trioxo-5-(1-pyridin-3-ylmethyl-piperidin-4-yl)-hexahydro-pyrimidin-5-ylmethyl]-benzamide;-   4-(2-methyl-quinolin-4-ylmethoxy)-N-{2,4,6-trioxo-5-[1-(tetrahydro-pyran-4-yl)-piperidin-4-yl]-hexahydro-pyrimidin-5-ylmethyl}-benzamide;-   N-[5-(1-acetyl-piperidin-4-yl)-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;-   N-{5-[1-(2,2-dimethyl-propionyl)-piperidin-4-yl]-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl}-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;    and-   4-(2-methyl-quinolin-4-ylmethoxy)-N-{2,4,6-trioxo-5-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-hexahydro-pyrimidin-5-ylmethyl}-benzamide;    or a pharmaceutically acceptable salt form thereof.    [8] Thus, in an embodiment, the present invention provides a novel    compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein;

-   A is C(═O), C(═S) or CH₂;-   B is O or S;-   L is O or S;-   W is selected from (CR^(a)R^(a1))_(m), C₂₋₃ alkenylene, and C₂₋₃    alkynylene;-   U is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH),    C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O, OC(O)NR^(a1),    NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1),    NR^(a1)S(O)_(p), and NR^(a1)SO₂NR^(a1);-   X is absent or is selected from C₁₋₃ alkylene, C₂₋₃ alkenylene, and    C₂₋₃ alkynylene;-   Y is absent or is selected from O, NR^(a1), S(O)_(p) and C(O);-   Z is absent or is selected from:    -   a C₃₋₁₃ carbocycle substituted with 0–5 R^(b); and    -   a 5–14 membered heterocycle comprising carbon atoms and 1–4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p), and substituted with 0–5 R^(b);-   U^(a) is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH),    C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O, OC(O)NR^(a1),    NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1),    NR^(a1)S(O)_(p), and NR^(a1)SO₂NR^(a1);-   X^(a) is absent or is selected from C₁₋₁₀ alkylene, C₂₋₁₀    alkenylene, and C₂₋₁₀ alkynylene;-   Y^(a) is absent or is selected from O, NR^(a1), S(O)_(p), and C(O);-   Z^(a) is selected from H, a C₃₋₁₃ carbocycle substituted with 0–5    R^(c), and a 5–14 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–5 R^(c);-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   provided that when Z is absent, Z^(a) is other than H;-   R¹ and R², together with the carbon atoms to which they are    attached, combine to form a 3–8 membered carbocyclic or heterocyclic    ring comprising carbon atoms, 0–2 ring heteroatoms selected from O,    N, NR¹⁰, and S(O)_(p), and 0–2 double bonds, and substituted with    0–3 R^(c); and the carbocyclic or heterocyclic ring is optionally    fused to a 5–6 membered carbocycle substituted with 0–3 R^(c) or a    5–6 membered heterocycle consisting of carbon atoms and 1–3    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–3 R^(c);-   R³ is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆    alkynylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)OC(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)OC(O)OR^(a1),    (CR^(a)R^(a1))_(r1)OC(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q, and    (CR^(a)R^(a1))_(r1)NR^(a)SO₂NR^(a)R^(a1);-   Q, at each occurrence, is independently selected from H, CHF₂, CH₂F,    CF₃, a C₃₋₁₃ carbocycle substituted with 0–5 R^(d), and a 5–14    membered heterocycle comprising carbon atoms and 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    substituted with 0–5 R^(d);-   R⁴ is selected from H, C₁₋₆ alkyl substituted with 0–1 R^(b), C₂₋₆    alkenyl substituted with 0–1 R^(b), and C₂₋₆ alkynyl substituted    with 0–1 R^(b);-   R⁵ is selected from H, C₁₋₆ alkyl substituted with 0–1 R^(b), C₂₋₆    alkenyl substituted with 0–1 R^(b), and C₂₋₆ alkynyl substituted    with 0–1 R^(b);-   n is 0 or 1;-   alternatively, when n is 1, R⁴ and R⁵, together with the carbon atom    to which they are attached, combine to form a 3–8 membered    carbocyclic or heterocyclic ring comprising carbon atoms, 0–2 ring    heteroatoms selected from O, N, NR^(c), and S(O)_(p), and 0–2 double    bonds, and substituted with 0–3 R^(c); and the carbocyclic or    heterocyclic ring is optionally fused to a 5–6 membered carbocycle    substituted with 0–3 R^(c) or a 5–6 membered heterocycle consisting    of carbon atoms and 1–3 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0–3 R^(c);-   R¹⁰, at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–2 R^(c1), C₂₋₆ alkenyl substituted with 0–2    R^(c1), C₂₋₆ alkynyl substituted with 0–2 R^(c1),    (CR^(a)R^(a1))_(s)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)OH,    (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)C(S)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(S)NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)OC(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(s)NR^(a)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a1),    (CR^(a)R^(a1))_(s)NR^(a)SO₂R^(a3),    (CR^(a)R^(a1))_(s)NR^(a)SO₂NR^(a)R^(a1), (CR^(a)R^(a1))_(r)—C₃₋₁₀    carbocycle substituted with 0–2 R^(c1), and (CR^(a)R^(a1))_(r)-5–14    membered heterocycle consisting of carbon atoms and 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    substituted with 0–2 R^(c1);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, and benzyl;-   R^(a1), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–1 R^(e), C₂₋₆ alkenyl substituted with 0–1    R^(e), C₂₋₆ alkynyl substituted with 0–1 R^(e), and —(CH₂)_(r)-3–8    membered carbocyclic or heterocyclic ring comprising carbon atoms    and 0–2 ring heteroatoms selected from N, NR^(a2), O, and S(O)_(p),    and substituted with 0–3 R^(e);-   alternatively, R^(a) and R^(a1), when attached to a nitrogen, are    taken together with the nitrogen to which they are attached, form a    5 or 6 membered heterocycle comprising carbon atoms and 0–1    additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p);-   R^(a2), at each occurrence, is independently selected from C₁₋₄    alkyl, phenyl, and benzyl;-   R^(a3), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–1 R^(c1), C₂₋₆ alkenyl substituted with 0–1    R^(c1), C₂₋₆ alkynyl substituted with 0–1 R^(c1), and —(CH₂)_(r)-3–8    membered carbocyclic or heterocyclic ring comprising carbon atoms    and 0–2 ring heteroatoms selected from N, NR^(a2), O, and S(O)_(p),    and substituted with 0–3 R^(c1);-   R^(b), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0–1 R^(c1), OR^(a), SR^(a), Cl, F, Br, I, ═O, —CN,    NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),    C(S)NR^(a)R^(a1), NR^(a)C(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1),    NR^(a)C(O)OR^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), NR^(aS(O))    ₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),    S(O)_(p)R^(a3), CF₃, CF₂CF₃, CHF₂, CH₂F, and phenyl;-   R^(c), at each occurrence, is independently selected from H, OR^(a),    Cl, F, Br, I, ═O, —CN, NO₂, CF₃, CF₂CF₃, CH₂F, CHF₂,    (CR^(a)R^(a1))_(r)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)C(═NCN)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)C(═NR^(a))NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)C(═NOR^(a))NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)OH, (CR^(a)R^(a1))_(r1)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(S)OR^(a1),    (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(S)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)OC(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3),    (CR^(a)R^(a1))_(r)NR^(a)SO₂NR^(a)R^(a1); C₁₋₆ alkyl substituted with    0–2 R^(c1); C₂₋₆ alkenyl substituted with 0–2 R^(c1); C₂₋₆ alkynyl    substituted with 0–2 R^(c1); (CR^(a)R^(a1))_(r)—C₃₋₁₀ carbocycle    substituted with 0–2 R^(c1); and (CR^(a)R^(a1))_(r)-5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–2 R^(c1);-   alternatively, when two R^(c) groups are attached to the same carbon    atom, they form a spiro ring C that is a 3–11 membered carbocycle or    heterocycle substituted with 0–2 R^(c1) and comprising: carbon    atoms, 0–4 ring heteroatoms selected from O, N, and S(O)_(p), and    0–2 double bonds, provided that ring C contains other than a S—S,    O—O, or S—O bond;-   alternatively, when two R^(c) groups are attached to adjacent carbon    atoms, together with the carbon atoms to which they are attached    they form a 5–7 membered carbocyclic or heterocyclic ring D    substituted with 0–2 R^(c1) and consisting of carbon atoms, 0–2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and 0–3 double bonds;-   R^(c1), at each occurrence, is independently selected from H, C₁₋₆    alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a),    C(O)OR^(a), C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1),    OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, OCF₃, CF₂CF₃, CH₂F, and    CHF₂;-   R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0–2 R^(e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl,    F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a),    C(O)NR^(a)R^(a1), C(S)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1),    OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a3), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(p)R^(a1),    NR^(a)S(O)₂R^(a3), S(O)_(a)R^(a3), CF₃CF₂CF₃, (CH₂)_(r)—C₃₋₁₀    carbocycle substituted with 0–2 R^(e), and a (CH₂)_(r)-5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–2 R^(e);-   R^(e), at each occurrence, is independently selected from H, C₁₋₆    alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a), C(O)R^(a),    C(O)OR^(a), C(O)NR^(a)R^(a), R^(a)NC(O)NR^(a)R^(a),    OC(O)NR^(a)R^(a), R^(a)NC(O)OR^(a), S(O)₂NR^(a)R^(a),    NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a), OS(O)₂NR^(a)R^(a),    NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, OCF₃, CF₂CF₃, CH₂F, and    CHF₂;-   m, at each occurrence, is selected from 0, 1, 2 and 3;-   p, at each occurrence, is selected from 0, 1, and 2;-   r, at each occurrence, is selected from 0, 1, 2, 3, and 4;-   r1, at each occurrence, is selected from 0, 1, 2, 3, and 4;-   s, at each occurrence, is selected from 2, 3, and 4; and-   provided that when A is C(═O), B is O, L is O, and R¹ and R²,    together with the carbon atoms to which they are attached, combine    to form 1,1-cyclopropyl,    -   (i) Z is absent, then Z^(a) is other than phenyl;    -   (ii) Z is phenylene, then Z^(a) is other than H.        [9] In another embodiment, the present invention provides a        novel compound, wherein;-   W is (CHR^(a))_(m) or C₂₋₃ alkenylene;-   U is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH),    C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), S(O)_(p), S(O)_(p)NR^(a1),    and NR^(a1)S(O)_(p);-   X is absent or C₁₋₃ alkylene;-   U^(a) is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH),    C(O)O, C(O)NR^(a1), NR^(a1)C(O), S(O)_(p), S(O)_(p)NR^(a1), and    NR^(a1)S(O)_(p);-   X^(a) is absent or is selected from C₁₋₄ alkylene, C₂₋₄ alkenylene,    and C₂₋₄ alkynylene;-   Y^(a) is absent or is selected from O and NR^(a1);-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   R¹ and R², together with the carbon atoms to which they are    attached, combine to form a 3–8 membered carbocyclic or heterocyclic    ring comprising carbon atoms, 0–2 ring heteroatoms selected from O,    N, NR¹⁰, and S(O)_(p), and 0–2 double bonds, and substituted with    0–3 R^(c);-   R³ is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆    alkynylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1)) )_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1), and    (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q;-   Q, at each occurrence, is independently selected from H, CF₃, a    C₃₋₁₃ carbocycle substituted with 0–5 R^(d), and a 5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–5 R^(d);-   R⁴ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;-   R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;-   n is 0 or 1;-   alternatively, when n is 1, R⁴ and R⁵, together with the carbon atom    to which they are attached, combine to form a 3–8 membered    carbocyclic or heterocyclic ring comprising carbon atoms, 0–2 ring    heteroatoms selected from O, N, NR¹⁰, and S(O)_(p), and 0–2 double    bonds, and substituted with 0–3 R^(c);-   R¹⁰, at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–2 R^(c1), C₂₋₆ alkenyl substituted with 0–2    R^(c1), C₂₋₆ alkynyl substituted with 0–2 R^(c1),    (CR^(a)R^(a1))_(s)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)SO₂R^(a3), (CR^(a)R^(a1))_(r)—C₃₋₁₀    carbocycle substituted with 0–2 R^(c1), and (CR^(a)R^(a1))_(r)-5–14    membered heterocycle consisting of carbon atoms and 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    substituted with 0–2 R^(c1);-   R^(c), at each occurrence, is independently selected from H, OR^(a),    Cl, F, Br, ═O, —CN, NO₂, NR^(a)R^(a1), CF₃,    (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₁₋₆ alkyl substituted with 0–1    R^(c1); C₂₋₆ alkenyl substituted with 0–1 R^(c1); C₂₋₆ alkynyl    substituted with 0–1 R^(c1); (CH₂)_(r)—C₃₋₆ carbocycle substituted    with 0–2 R^(c1); and (CH₂)_(r)-5–6 membered heterocycle comprising    carbon atoms and 1–4 heteroatoms selected from the group consisting    of N, O, and S(O)_(p), and substituted with 0–2 R^(c1);-   alternatively, when two R^(c) groups are attached to the same carbon    atom, they form a spiro ring C that is a 3–8 membered carbocycle or    heterocycle substituted with 0–2 R^(c1) and comprising: carbon    atoms, 0–4 ring heteroatoms selected from O, N, and S(O)_(p), and    0–2 double bonds, provided that ring C contains other than a S—S,    O—O, or S—O bond; and-   alternatively, when two R^(c) groups are attached to adjacent carbon    atoms, together with the carbon atoms to which they are attached,    form a 5–7 membered carbocyclic or heterocyclic ring D substituted    with 0–2 R^(c1) and consisting of carbon atoms, 0–2 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and 0–3    double bonds.    [10] In another embodiment, the present invention provides a novel    compound, wherein;-   A is C(═O) or CH₂;-   B is O;-   L is O;-   U is absent or is selected from: O, NR^(a1), C(O), C(O)NR^(a1),    NR^(a1)C(O), S(O)_(p), S(O)_(p)NR^(a1), and NR^(a1)S(O)_(p);-   X is absent, methylene or ethylene;-   Z is absent or is selected from:    -   a C₃₋₈ cycloalkyl substituted with 0–5 R^(b);    -   a C₃₋₈ cycloalkenyl substituted with 0–5 R^(b);    -   phenyl substituted with 0–5 R^(b);    -   naphthyl substituted with 0–5 R^(b); and    -   a 5–14 membered heterocycle comprising carbon atoms and 1–4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p), and substituted with 0–5 R^(b);-   U^(a), is absent or is selected from: O, NR^(a1), C(O), C(O)NR^(a1),    NR^(a1)C(O), S(O)_(p), S(O)_(p)NR^(a1), and NR^(a1)S(O)_(p);-   Z^(a) is selected from H, a C₅₋₁₀ carbocycle substituted with 0–5    R^(c), and a 5–14 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–5 R^(c);-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   provided that when Z is absent, Z^(a) is other than H;-   R³ is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆    alkynylene-Q,    (CR^(a)R^(a1))_(r1)OR^(a1)(CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   Q, at each occurrence, is independently selected from H, a C₃₋₁₀    carbocycle substituted with 0–3 R^(d), and a 5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–3 R^(d);-   R⁴ is selected from H and C₁₋₆ alkyl;-   R⁵ is selected from H and C₁₋₆ alkyl;-   R¹⁰, at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–1 R^(c1), C₂₋₆ alkenyl substituted with 0–1    R^(c1), C₂₋₆ alkynyl substituted with 0–1 R^(c1),    (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)—C₃₋₆ carbocycle substituted with 0–2 R^(c1), and    (CR^(a)R^(a1))_(r)-5–10 membered heterocycle consisting of carbon    atoms and 1–4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), and substituted with 0–2 R^(c1);-   R^(a), at each occurrence, is independently selected from H and C₁₋₆    alkyl;-   R^(a1), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl;-   alternatively, R^(a) and R^(a1), when attached to a nitrogen, are    taken together with the nitrogen to which they are attached, form a    5 or 6 membered heterocycle comprising carbon atoms and 0–1    additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p);-   R^(a3), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, and —(CH₂)_(r)-^(3–8) membered carbocyclic or    heterocyclic ring comprising carbon atoms and 0–2 ring heteroatoms    selected from N, NR^(a2), O, and S(O)_(p) and substituted with 0–3    R^(c1);-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₃₋₆ carbocycle substituted with    0–2 R^(c1); and 5–6 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0–2 R^(c1);-   alternatively, when two R^(c) groups are attached to the same carbon    atom, they form a spiro ring C that is a 3–8 membered carbocycle or    heterocycle substituted with 0–2 R^(c1) and comprising: carbon    atoms, 0–4 ring heteroatoms selected from O, N, and S(O)_(p), and    0–2 double bonds, provided that ring C contains other than a S—S,    O—O, or S—O bond;-   alternatively, when two R^(c) groups are attached to adjacent carbon    atoms, together with the carbon atoms to which they are attached    they form a 5–6 membered carbocyclic or heterocyclic ring D    substituted with 0–2 R^(c1) and consisting of carbon atoms, 0–2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and 0–3 double bonds;-   R^(c1), at each occurrence, is independently selected from H, C₁₋₄    alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂, C(O)OR^(a), and    C(O)NR^(a)R^(a1);-   R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0–2 R^(e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl,    F, Br, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a),    C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),    S(O)_(p)R^(a3), CF₃, (CH₂)_(r)—C₃₋₆ carbocycle substituted with 0–2    R^(e), and a 5–6 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p); and-   R^(e), at each occurrence, is independently selected from H, C₁₋₄    alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂, C(O)OR^(a), and    C(O)NR^(a)R^(a).    [11] In another embodiment, the present invention provides a novel    compound, wherein;-   W is (CH₂)_(m) or C₂₋₃ alkenylene;-   Z is absent or selected from:    -   a C₄₋₈ cycloalkyl substituted with 0–3 R^(b);    -   a C₄₋₈ cycloalkenyl substituted with 0–3 R^(b);    -   phenyl substituted with 0–3 R^(b);    -   naphthyl substituted with 0–3 R^(b);    -   a 5–10 membered heterocycle comprising carbon atoms and 1–4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p) and substituted with 0–3 R^(b); and said 5–10 membered        heterocycle is selected from the group: furanyl,        tetrahydrofuranyl, thiazolyl, oxazolyl, imidazolyl,        isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl, thiophenyl,        triazinyl, pyridyl, pyrimidinyl, piperazinyl, piperidinyl,        pyranyl, pyrazinyl, pyrazolyl, pyridoimidazole, pyrrolidinyl,        pyrrolinyl, indolyl, indolinyl, benzimidazolyl, benzothiazinyl,        benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,        benztriazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl,        tetrahydroquinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl,        indazolyl, isobenzofuranyl, isoindazolyl, isoindolinyl,        isoindolyl, isoquinolinyl, methylenedioxyphenyl, quinazolinyl,        thiadiazinyl, and        1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl;-   Z^(a) is selected from: H;    -   phenyl substituted with 0–3 R^(c);    -   naphthyl substituted with 0–3 R^(c); and a 5–10 membered        heterocycle comprising carbon atoms and 1–4 heteroatoms selected        from the group consisting of N, O, and S(O)_(p) and substituted        with 0–3 R^(c); and said 5–10 membered heterocycle is selected        from the group: furanyl, tetrahydrofuranyl, thiazolyl, oxazolyl,        imidazolyl, isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl,        thiophenyl, triazinyl, pyridyl, pyrimidinyl, piperazinyl,        piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridoimidazole,        pyrrolidinyl, pyrrolinyl, indolyl, indolinyl, benzimidazolyl,        benzothiazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl,        benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl,        quinolinyl, tetrahydroquinolinyl, isoquinolinyl,        tetrahydro-isoquinolinyl, indazolyl, isobenzofuranyl,        isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,        methylenedioxyphenyl, quinazolinyl, thiadiazinyl, and        1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl;-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   provided that when Z is absent, Z^(a) is other than H;-   R¹ and R², together with the carbon atoms to which they are    attached, combine to form a 4–7 membered carbocyclic or heterocyclic    ring comprising carbon atoms, 0–2 ring heteroatoms selected from O,    N, NR¹⁰, and S(O)_(p), and 0–2 double bonds, and substituted with    0–3 R^(c);-   R³ is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q,    (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   Q, at each occurrence, is independently selected from H, a C₃₋₆    carbocycle substituted with 0–3 R^(d), and a 5–10 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0–3 R^(d);-   R^(a), at each occurrence, is independently selected from H and C₁₋₆    alkyl;-   R^(a1), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl;-   R^(a3), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, and benzyl;-   R^(b), at each occurrence, is independently selected from C₁₋₄    alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),    C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a3), and CF₃;-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₃₋₆ carbocycle substituted with    0–2 R^(c1); and 5–6 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0–2 R^(c1); and-   R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0–1 R^(e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl,    F, Br, ═O, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a), C(O)NR^(a)R^(a1),    S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, and    (CH₂)_(r)-phenyl substituted with 0–2 R^(e).    [12] In another embodiment, the present invention provides a novel    compound, wherein;-   X is absent or is methylene;-   Y is absent or is O;-   Z is absent or is selected from:    -   phenyl substituted with 0–3 R^(b);    -   naphthyl substituted with 0–3 R^(b);    -   thiophenyl substituted with 0–2 R^(b);    -   oxazolyl substituted with 0–1 R^(b);    -   isoxazolyl substituted with 0–1 R^(b); and    -   thiazolyl substituted with 0–1 R^(b);-   U^(a) is absent or is O;-   Y^(a) is absent or is O;-   Z^(a) is selected from: H;    -   phenyl substituted with 0–3 R^(c);    -   pyridyl substituted with 0–3 R^(c);    -   indolyl substituted with 0–3 R^(c);    -   quinolinyl substituted with 0–3 R^(c);    -   benzimidazolyl substituted with 0–3 R^(c); and    -   1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl substituted        with 0–3 R^(c);-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   provided that when Z is absent, Z^(a) is other than H;-   R¹ and R², together with the carbon atoms to which they are    attached, combine to form a 5–6 membered carbocyclic or heterocyclic    ring comprising carbon atoms, 0–2 ring heteroatoms selected from O,    N, NR¹⁰, and S(O)_(p), and 0–2 double bonds, and substituted with    0–3 R^(c);-   R³ is selected from Q, C₁₋₆ alkylene-Q,    (CR^(a)R^(a1))_(r1)OR^(a1)(CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(s)—Q, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   R⁴ is selected from H and C₁₋₄ alkyl;-   R⁵ is selected from H and C₁₋₄ alkyl;-   n is 0 or 1;-   R¹⁰, at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–1 R^(c1), C₂₋₆ alkenyl substituted with 0–1    R^(c1), C₂₋₆ alkynyl substituted with 0–1 R^(c1),    (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)S(O) pR^(a3),    (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1), (CR^(a)R^(a1))_(r)—C₃₋₆    carbocycle substituted with 0–2 R^(c1), and (CR^(a)R^(a1))_(r)-5–6    membered heterocycle consisting of carbon atoms and 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p) and    substituted with 0–2 R^(c1); and-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    and phenyl.    [13] In another embodiment, the present invention provides a novel    compound, wherein;-   R³ is selected from Q, C₁₋₆ alkylene-Q, C(O)(CR^(a)R^(a1))_(r)-Q,    C(O)OR^(a1), C(O)NR^(a)R^(a1), C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q, and    S(O)_(p)(CR^(a)R^(a1))_(r)-Q;-   Q, at each occurrence, is independently selected from H, cyclopropyl    substituted with 0–1 R^(d), cyclopentyl substituted with 0–1 R^(d),    cyclohexyl substituted with 0–1 R^(d), phenyl substituted with 0–2    R^(d), and a heteroaryl substituted with 0–3 R^(d), wherein the    heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl,    imidazolyl, and isoxazolyl;-   R⁴ is selected from H, methyl, and ethyl;-   R⁵ is selected from H, methyl, and ethyl;-   R^(a2), at each occurrence, is independently selected from H,    methyl, and ethyl;-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    and (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3); and-   r, at each occurrence, is selected from 0, 1, 2, and 3.    [14] In another preferred embodiment, the present invention provides    a novel compound selected from the group:-   4-[(2-methyl-4-quinolinyl)methoxy]-N-(1,3,5-trioxo-2,4-diazaspiro[5.5]undec-7-yl)benzamide    trifluoroacetate;-   4-[(2-methyl-4-quinolinyl)methoxy]-N-(6,8,10-trioxo-7,9-diazaspiro[4.5]dec-1-yl)benzamide    trifluoroacetate;-   4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzoylamino]-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]decane-2-carboxylic    acid tert-butyl ester;-   4-[4-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[1,4]thiazin-4-ylmethyl)-benzoylamino]-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]decane-2-carboxylic    acid tert-butyl ester;-   4-[4-(2-isopropyl-benzoimidazol-1-ylmethyl)-benzoylamino]-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]decane-2-carboxylic    acid tert-butyl ester;-   4-[4-(2-methyl-quinolin-4-ylmethyl)-benzoylamino]-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]decane-2-carboxylic    acid tert-butyl ester;-   4-(2-methyl-quinolin-4-.ylmethoxy)-N-(6,8,10-trioxo-2-oxa-7,9-diaza-spiro[4.5]dec-4-yl)-benzamide;-   7-[4-(2-methyl-quinolin-4-ylmethoxy)-benzoylamino]-1,3,5-trioxo-2,4,9-triaza-spiro[5.5]undecane-9-carboxylic    acid tert-butyl ester;-   N-(2-acetyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;-   N-(2-methanesulfonyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;-   N-[2-(2,2-dimethyl-propionyl)-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;-   4-(2-methyl-quinolin-4-ylmethoxy)-N-[6,8,10-trioxo-2-(pyridine-3-carbonyl)-2,7,9-triaza-spiro[4.5]dec-4-yl]-benzamide;-   N-(2-acetyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-methyl-quinolin-4-ylmethyl)-benzamide;-   N-(2-methanesulfonyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-methyl-quinolin-4-ylmethyl)-benzamide-   N-(2-acetyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-isopropyl-benzoimidazol-1-ylmethyl)-benzamide;-   4-(2-isopropyl-benzoimidazol-1-ylmethyl)-N-(2-methanesulfonyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-benzamide;-   N-(2-acetyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[1,4]thiazin-4-ylmethyl)-benzamide;-   4-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[1,4]thiazin-4-ylmethyl)-N-(2-methanesulfonyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-benzamide;    and-   1-(4-phenoxy)phenyl-5,7-diazaspiro[2.5]octane-4,6,8-trione;    or a pharmaceutically acceptable salt form thereof.    [15] Thus, in an embodiment, the present invention provides a novel    compound of formula II:

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein;

-   A is C(═O), C(═S) or CH₂;-   B is O or S;-   L is O or S;-   W is selected from (CR^(a)R^(a1))_(m), C₂₋₃ alkenylene, and C₂₋₃    alkynylene;-   U is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH),    C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O, OC(O)NR^(a1),    NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1),    NR^(a1)S(O)_(p), and NR^(a1)SO₂NR^(a1);-   X is absent or is selected from C₁₋₃ alkylene, C₂₋₃ alkenylene, and    C₂₋₃ alkynylene;-   Y is absent or is selected from O, NR^(a1), S(O)_(p) and C(O);-   Z is absent or is selected from:    -   a C₃₋₁₃ carbocycle substituted with 0–5 R^(b); and    -   a 5–14 membered heterocycle comprising carbon atoms and 1–4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p) and substituted with 0–5 R^(b);-   U^(a) is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH),    C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O, OC(O)NR^(a1),    NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1),    NR^(a1)S(O)_(p), and NR^(a1)SO₂NR^(a1);-   X^(a) is absent or is selected from C₁₋₁₀ alkylene, C₂₋₁₀    alkenylene, and C₂₋₁₀ alkynylene;-   Y^(a) is absent or is selected from O, NR^(a1), S(O)_(p), and C(O);-   Z^(a) is selected from H, a C₃₋₁₃ carbocycle substituted with 0–5    R^(c), and a 5–14 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0–5 R^(c);-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   provided that when Z is absent, Z^(a) is other than H;-   R¹ and R⁴, together with the carbon atoms to which they are    attached, combine to form a 3–8 membered carbocyclic or heterocyclic    ring comprising carbon atoms, 0–2 ring heteroatoms selected from O,    N, NR¹⁰, and S(O)_(p), and 0–2 double bonds, and substituted with    0–3 R^(c); and the carbocyclic or heterocyclic ring is optionally    fused to a 5–6 membered carbocycle substituted with 0–3 R^(c) or a    5–6 membered heterocycle consisting of carbon atoms and 1–3    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0–3 R^(c);-   R² is selected from Q¹, C₁₋₆ alkylene-Q¹, C₂₋₆ alkenylene-Q¹, C₂₋₆    alkynylene-Q¹, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q¹, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   Q¹, at each occurrence, is independently selected from H, a C₃₋₁₃    carbocycle substituted with 0–5 R^(d), and a 5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0–5 R^(d);-   R³ is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆    alkynylene-Q,    (CR^(a)R^(a1))_(r1)OR^(a1)(CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)OC(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)OC(O)OR^(a1),    (CR^(a)R^(a1))_(r1)OC(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q, and    (CR^(a)R^(a1))_(r1)NR^(a)SO₂NR^(a)R^(a1);-   Q, at each occurrence, is independently selected from H, CHF₂, CH₂F,    CF₃, a C₃₋₁₃ carbocycle substituted with 0–5 R^(d), and a 5–14    membered heterocycle comprising carbon atoms and 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p) and    substituted with 0–5 R^(d);-   R⁵ is selected from H, C₁₋₆ alkyl substituted with 0–1 R^(b), C₂₋₆    alkenyl substituted with 0–1 R^(b), and C₂₋₆ alkynyl substituted    with 0–1 R^(b);-   R¹⁰, at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–2 R^(c1), C₂₋₆ alkenyl substituted with 0–2    R^(c1), C₂₋₆ alkynyl substituted with 0–2 R^(c1),    (CR^(a)R^(a1))_(s)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)OH,    (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)C(S)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(S)NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)OC(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(s)NR^(a)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)SO₂R^(a3),    (CR^(a)R^(a1))_(s)NR^(a)SO₂NR^(a)R^(a1), (CR^(a)R^(a1))_(r)—C₃₋₁₀    carbocycle substituted with 0–2 R^(c1), and (CR^(a)R^(a1))_(r)-5–14    membered heterocycle consisting of carbon atoms and 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p) and    substituted with 0–2 R^(c1);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, and benzyl;-   R^(a1), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–1 R^(e), C₂₋₆ alkenyl substituted with 0–1    R^(e), C₂₋₆ alkynyl substituted with 0–1 R^(e), and —(CH₂)_(r)-3–8    membered carbocyclic or heterocyclic ring comprising carbon atoms    and 0–2 ring heteroatoms selected from N, NR^(a2), O, and S(O)_(p)    and substituted with 0–3 R^(e);-   alternatively, R^(a) and R^(a1), when attached to a nitrogen, are    taken together with the nitrogen to which they are attached, form a    5 or 6 membered heterocycle comprising carbon atoms and 0–1    additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p);-   R^(a2), at each occurrence, is independently selected from C₁₋₄    alkyl, phenyl, and benzyl;-   R^(a3), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–1 R^(c1), C₂₋₆ alkenyl substituted with 0–1    R^(c1), C₂₋₆ alkynyl substituted with 0–1 R^(c1), and —(CH₂)_(r)-3–8    membered carbocyclic or heterocyclic ring comprising carbon atoms    and 0–2 ring heteroatoms selected from N, NR^(a2), O, and S(O)_(p)    and substituted with 0–3 R^(c1);-   R^(b), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0–1 R^(c1), OR^(a), SR^(a), Cl, F, Br, I, ═O, —CN,    NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),    C(S)NR^(a)R^(a1), NR^(a)C(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1),    NR^(a)C(O)OR^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),    NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),    S(O)_(p)R^(a3), CF₃, CF₂CF₃, CHF₂, CH₂F, and phenyl;-   R^(c), at each occurrence, is independently selected from H, OR^(a),    Cl, F, Br, I, ═O, —CN, NO₂, CF₃, CF₂CF₃, CH₂F, CHF₂,    (CR^(a)R^(a1))_(r)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)C(═NCN)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)C(═NR^(a))NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)C(═NOR^(a))NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)OH, (CR^(a)R^(a1))_(r1)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(S)OR^(a1),    (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(S)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)OC(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3), and    (CR^(a)R^(a1))_(r)NR^(a)SO₂NR^(a)R^(a1); C₁₋₆ alkyl substituted with    0–2 R^(c1); C₂₋₆ alkenyl substituted with 0–2 R^(c1); C₂₋₆ alkynyl    substituted with 0–2 R^(c1); (CR^(a)R^(a1))_(r)—C₃₋₁₀ carbocycle    substituted with 0–2 R^(c1); and (CR^(a)R^(a1))_(r)-5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0–2 R^(c1);-   alternatively, when two R^(c) groups are attached to the same carbon    atom, they form a spiro ring C that is a 3–11 membered carbocycle or    heterocycle substituted with 0–2 R^(c1) and comprising: carbon    atoms, 0–4 ring heteroatoms selected from O, N, and S(O)_(p), and    0–2 double bonds, provided that ring C contains other than a S—S,    O—O, or S—O bond;-   alternatively, when two R^(c) groups are attached to adjacent carbon    atoms, together with the carbon atoms to which they are attached    they form a 5–7 membered carbocyclic or heterocyclic ring D    substituted with 0–2 R^(c1) and consisting of carbon atoms, 0–2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and 0–3 double bonds;-   R^(c1), at each occurrence, is independently selected from H, C₁₋₆    alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a),    C(O)OR^(a), C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1),    OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, OCF₃, CF₂CF₃, CH₂F, and    CHF₂;-   R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0–2 R^(e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl,    F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a),    C(O)NR^(a)R^(a1), C(S)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1),    OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a3), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, CF₂CF₃, (CH₂)_(r)—C₃₋₁₀    carbocycle substituted with 0–2 R^(e), and a (CH₂)_(r)-5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0–2 R^(e);-   R^(e), at each occurrence, is independently selected from H, C₁₋₆    alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a), C(O)R^(a),    C(O)OR^(a), C(O)NR^(a)R^(a), R^(a)NC(O)NR^(a)R^(a),    OC(O)NR^(a)R^(a), R^(a)NC(O)OR^(a), S(O)₂NR^(a)R^(a),    NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a), OS(O)₂NR^(a)R^(a),    NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, OCF₃, CF₂CF₃, CH₂F, and    CHF₂;-   m, at each occurrence, is selected from 0, 1, 2 and 3;-   p, at each occurrence, is selected from 0, 1, and 2;-   r, at each occurrence, is selected from 0, 1, 2, 3, and 4;-   r1, at each occurrence, is selected from 0, 1, 2, 3, and 4;-   s, at each occurrence, is selected from 2, 3, and 4; and-   provided that when A is C(═O), B is O, L is O, and R¹ and R⁴,    together with the carbon atoms to which they are attached, combine    to form a 1,3-cyclobutane,    -   (i) Z is absent, then Z^(a) is other than spiro[3.3]heptane;    -   (ii) Z is spiro[3.3]heptane, then Z^(a) is other than H.        [16] In another embodiment, the present invention provides a        novel compound, wherein;-   W is (CHR^(a))_(m) or C₂₋₃ alkenylene;-   U is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH),    C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), S(O)_(p), S(O)_(p)NR^(a1),    and NR^(a1)S(O)_(p);-   X is absent or C₁₋₃ alkylene;-   U^(a) is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH),    C(O)O, C(O)NR^(a1), NR^(a1)C(O), S(O)_(p), S(O)_(p)NR^(a1), and    NR^(a1)S(O)_(p);-   X^(a) is absent or is selected from C₁₋₄ alkylene, C₂₋₄ alkenylene,    and C₂₋₄ alkynylene;-   Y^(a) is absent or is selected from O and NR^(a1);-   R¹ and R⁴, together with the carbon atoms to which they are    attached, combine to form a 3–8 membered carbocyclic or heterocyclic    ring comprising carbon atoms, 0–2 ring heteroatoms selected from O,    N, NR¹⁰, and S(O)_(p), and 0–2 double bonds, and substituted with    0–3 R^(c);-   R² is selected from Q¹, C₁₋₆ alkylene-Q¹, C₂₋₆ alkenylene-Q¹, C₂₋₆    alkynylene-Q¹,    (CR^(a)R^(a1))_(r1)OR^(a1)(CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q¹, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   Q¹, at each occurrence, is independently selected from H, a C₃₋₁₀    carbocycle substituted with 0–5 R^(d), and a 5–10 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0–5 R^(d);-   R³ is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆    alkynylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1), and    (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q;-   Q, at each occurrence, is independently selected from H, CF₃, a    C₃₋₁₃ carbocycle substituted with 0–5 R^(d), and a 5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0–5 R^(d);-   R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;-   R¹⁰, at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–2 R^(c1), C₂₋₆ alkenyl substituted with 0–2    R^(c1), C₂₋₆ alkynyl substituted with 0–2 R^(c1),    (CR^(a)R^(a1))_(s)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(s)NR^(a)SO₂R^(a3), (CR^(a)R^(a1))_(r)—C₃₋₁₀    carbocycle substituted with 0–2 R^(c1), and (CR^(a)R^(a1))_(r)-5–14    membered heterocycle consisting of carbon atoms and 1–4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p) and    substituted with 0–2 R^(c1);-   R^(c), at each occurrence, is independently selected from H, OR^(a),    Cl, F, Br, ═O, —CN, NO₂, NR^(a)R^(a1), CF₃,    (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₁₋₆ alkyl substituted with 0–1    R^(c1); C₂₋₆ alkenyl substituted with 0–1 R^(c1); C₂₋₆ alkynyl    substituted with 0–1 R^(c1); (CH₂)_(r)—C₃₋₆ carbocycle substituted    with 0–2 R^(c1); and (CH₂)_(r)-5–6 membered heterocycle comprising    carbon atoms and 1–4 heteroatoms selected from the group consisting    of N, O, and S(O)_(p) and substituted with 0–2 R^(c1);-   alternatively, when two R^(c) groups are attached to the same carbon    atom, they form a spiro ring C that is a 3–8 membered carbocycle or    heterocycle substituted with 0–2 R^(c1) and comprising: carbon    atoms, 0–4 ring heteroatoms selected from O, N, and S(O)_(p), and    0–2 double bonds, provided that ring C contains other than a S—S,    O—O, or S—O bond; and-   alternatively, when two R^(c) groups are attached to adjacent carbon    atoms, together with the carbon atoms to which they are attached    they form a 5–7 membered carbocyclic or heterocyclic ring D    substituted with 0–2 R^(c1) and consisting of carbon atoms, 0–2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and 0–3 double bonds.    [17] In another embodiment, the present invention provides a novel    compound, wherein;-   A is C(═O) or CH₂;-   B is O;-   L is O;-   U is absent or is selected from: O, NR^(a1), C(O), C(O)NR^(a1),    NR^(a1)C(O), S(O)_(p), S(O)_(p)NR^(a1), and NR^(a1)S(O)_(p);-   X is absent, methylene or ethylene;-   Z is absent or is selected from:    -   a C₃₋₈ cycloalkyl substituted with 0–5 R^(b);    -   a C₃₋₈ cycloalkenyl substituted with 0–5 R^(b);    -   phenyl substituted with 0–5 R^(b);    -   naphthyl substituted with 0–5 R^(b); and    -   a 5–14 membered heterocycle comprising carbon atoms and 1–4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p) and substituted with 0–5 R^(b);-   U^(a) is absent or is selected from: O, NR^(a1), C(O), C(O)NR^(a1),    NR^(a1)C(O), S(O)_(p), S(O)_(p)NR^(a1), and NR^(a1)S(O)_(p);-   Z^(a) is selected from H, a C₅₋₁₀ carbocycle substituted with 0–5    R^(c), and a 5–14 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0–5 R^(c);-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   provided that when Z is absent, Z^(a) is other than H;-   R² is selected from Q¹, C₁₋₆ alkylene-Q¹, C₂₋₆ alkenylene-Q¹,    (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q¹,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q¹, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   Q¹, at each occurrence, is independently selected form H, a C₃₋₆    carbocycle substituted with 0–3 R^(d), and a 5–10 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0–3 R^(d);-   R³ is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆    alkynylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   Q, at each occurrence, is independently selected form H, a C₃₋₁₀    carbocycle substituted with 0–3 R^(d), and a 5–14 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0–3 R^(d);-   R⁵ is selected from H and C₁₋₆ alkyl;-   R¹⁰, at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–1 R^(c1), C₂₋₆ alkenyl substituted with 0–1    R^(c1), C₂₋₆ alkynyl substituted with 0–1 R^(c1),    (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)—C₃₋₆ carbocycle substituted with 0–2 R^(c1), and    (CR^(a)R^(a1))_(r)-5–10 membered heterocycle consisting of carbon    atoms and 1–4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p) and substituted with 0–2 R^(c1);-   R^(a), at each occurrence, is independently selected from H and C₁₋₆    alkyl;-   R^(a1) ¹ at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl;-   alternatively, R^(a) and R^(a1), when attached to a nitrogen, are    taken together with the nitrogen to which they are attached, form a    5 or 6 membered heterocycle comprising carbon atoms and 0–1    additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p);-   R^(a3), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, and —(CH₂)_(r)-3–8 membered carbocyclic or    heterocyclic ring comprising carbon atoms and 0–2 ring heteroatoms    selected from N, NR^(a2), O, and s(O)_(p) and substituted with 0–3    R^(c1);-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₃₋₆ carbocycle substituted with    0–2 R^(c1); and 5–6 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0–2 R^(c1);-   alternatively, when two R^(c) groups are attached to the same carbon    atom, they form a spiro ring C that is a 3–8 membered carbocycle or    heterocycle substituted with 0–2 R^(c1) and comprising: carbon    atoms, 0–4 ring heteroatoms selected from O, N, and S(O)_(p), and    0–2 double bonds, provided that ring C contains other than a S—S,    O—O, or S—O bond;-   alternatively, when two R^(c) groups are attached to adjacent carbon    atoms, together with the carbon atoms to which they are attached    they form a 5–6 membered carbocyclic or heterocyclic ring D    substituted with 0–2 R^(c1) and consisting of carbon atoms, 0–2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and 0–3 double bonds;-   R^(c1), at each occurrence, is independently selected from H, C₁₋₄    alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂, C(O)OR^(a), and    C(O)NR^(a)R^(a1);-   R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0–2 R^(e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl,    F, Br, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a),    C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),    S(O)_(p)R^(a3), CF₃, (CH₂)_(r)—C₃₋₆ carbocycle substituted with 0–2    R^(e), and a 5–6 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p); and-   R^(e), at each occurrence, is independently selected from H, C₁₋₄    alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂, C(O)OR^(a), and    C(O)NR^(a)R^(a).    [18] In another embodiment, the present invention provides a novel    compound, wherein;-   W is (CH₂)_(m) or C₂₋₃ alkenylene;-   Z is absent or is selected from:    -   a C₄₋₈ cycloalkyl substituted with 0–3 R^(b);    -   a C₄₋₈ cycloalkenyl substituted with 0–3 R^(b);    -   phenyl substituted with 0–3 R^(b);    -   naphthyl substituted with 0–3 R^(b); a 5–10 membered heterocycle        comprising carbon atoms and 1–4 heteroatoms selected from the        group consisting of N, O, and S(O)_(p) and substituted with 0–3        R^(b); and said 5–10 membered heterocycle is selected from the        group: furanyl, tetrahydrofuranyl, thiazolyl, oxazolyl,        imidazolyl, isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl,        thiophenyl, triazinyl, pyridyl, pyrimidinyl, piperazinyl,        piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridoimidazole,        pyrrolidinyl, pyrrolinyl, indolyl, indolinyl, benzimidazolyl,        benzothiazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl,        benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl,        quinolinyl, tetrahydroquinolinyl, isoquinolinyl,        tetrahydro-isoquinolinyl, indazolyl, isobenzofuranyl,        isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,        methylenedioxyphenyl, quinazolinyl, thiadiazinyl, and        1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl;-   Z^(a) is selected from: H;    -   phenyl substituted with 0–3 R^(c);    -   naphthyl substituted with 0–3 R^(c); and a 5–10 membered        heterocycle comprising carbon atoms and 1–4 heteroatoms selected        from the group consisting of N, O, and S(O)_(p) and substituted        with 0–3 R^(c); and said 5–10 membered heterocycle is selected        from the group: furanyl, tetrahydrofuranyl, thiazolyl, oxazolyl,        imidazolyl, isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl,        thiophenyl, triazinyl, pyridyl, pyrimidinyl, piperazinyl,        piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridoimidazole,        pyrrolidinyl, pyrrolinyl, indolyl, indolinyl, benzimidazolyl,        benzothiazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl,        benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl,        quinolinyl, tetrahydroquinolinyl, isoquinolinyl,        tetrahydro-isoquinolinyl, indazolyl, isobenzofuranyl,        isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,        methylenedioxyphenyl, quinazolinyl, thiadiazinyl, and        1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl;-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   provided that when Z is absent, Z^(a) is other than H;-   R¹ and R⁴, together with the carbon atoms to which they are    attached, combine to form a 4–7 membered carbocyclic or heterocyclic    ring comprising carbon atoms, 0–2 ring heteroatoms selected from O,    N, NR¹⁰, and S(O)_(p), and 0–2 double bonds, and substituted with    0–3 R^(c);-   R³ is selected from Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q,    (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r1)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   Q, at each occurrence, is independently selected from H, a C₃₋₆    carbocycle substituted with 0–3 R^(d), and a 5–10 membered    heterocycle comprising carbon atoms and 1–4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0–3 R^(d);-   R^(a), at each occurrence, is independently selected from H and C₁₋₆    alkyl;-   R^(a1), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, benzyl, 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl;-   R^(a3), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, and benzyl;-   R^(b), at each occurrence, is independently selected from C₁₋₄    alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),    C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a3), and CF₃;-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₃₋₆ carbocycle substituted with    0–2 R^(c1); and 5–6 membered heterocycle comprising carbon atoms and    1–4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0–2 R^(c1); and-   R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0–1 R^(e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl,    F, Br, ═O, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a), C(O)NR^(a)R^(a1),    S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, and    (CH₂)_(r)-phenyl substituted with 0–2 R^(e); and-   provided that when A is C(═O), B is O, L is O, and R¹ and R⁴,    together with the carbon atoms to which they are attached, combine    to form a 1,3-cyclobutane, and Z is spiro[3.3]heptane, then Z^(a) is    other than H.    [19] In another embodiment, the present invention provides a novel    compound, wherein;-   X is absent or is methylene;-   Y is absent or is O;-   Z is absent or is selected from:    -   phenyl substituted with 0–3 R^(b);    -   naphthyl substituted with 0–3 R^(b);    -   thiophenyl substituted with 0–2 R^(b);    -   oxazolyl substituted with 0–1 R^(b);    -   isoxazolyl substituted with 0–1 R^(b); and    -   thiazolyl substituted with 0–1 R^(b);-   U^(a) is absent or is O;-   Y^(a) is absent or is O;-   Z^(a) is selected from: H;    -   phenyl substituted with 0–3 R^(c);    -   pyridyl substituted with 0–3 R^(c);    -   indolyl substituted with 0–3 R^(c);    -   quinolinyl substituted with 0–3 R^(c);    -   benzimidazolyl substituted with 0–3 R^(c); and    -   1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl substituted        with 0–3 R^(c);-   provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine to    form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or    S(O)_(p)—S(O)_(p) group;-   provided that when Z is absent, Z^(a) is other than H;-   R¹ and R⁴, together with the carbon atoms to which they are    attached, combine to form a 5–6 membered carbocyclic or heterocyclic    ring comprising carbon atoms, 0–2 ring heteroatoms selected from O,    N, NR¹⁰, and S(O)_(p), and 0–2 double bonds, and substituted with    0–3 R^(c);-   R² is selected from Q¹, C₁₋₆ alkylene-Q¹, C(O)NR^(a)R^(a1),    C(O)(CR^(a)R^(a1))_(r)-Q¹, C(O)OR^(a1), and    S(O)_(p)(CR^(a)R^(a1))_(r)-Q¹;-   Q¹, at each occurrence, is independently selected from H, a    cyclopropyl substituted with 0–1 R^(d), cyclopentyl substituted with    0–1 R^(d), cyclohexyl substituted with 0–1 R^(d), phenyl substituted    with 0–2 R^(d), and a heteroaryl substituted with 0–3 R^(d), wherein    the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl,    furanyl, imidazolyl, and isoxazolyl;-   R³ is selected from Q, C₁₋₆ alkylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(s)—Q, and    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1);-   R⁵ is selected from H and C₁₋₄ alkyl;-   R¹⁰, at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0–1 R^(c1), C₂₋₆ alkenyl substituted with 0–1    R^(c1), C₂₋₆ alkynyl substituted with 0–1 R^(c1),    (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)—C₃₋₆ carbocycle substituted with 0–2 R^(c1), and    (CR^(a)R^(a1))_(r)-5–6 membered heterocycle consisting of carbon    atoms and 1–4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p) and substituted with 0–2 R^(c1); and-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    and phenyl.    [20] In another embodiment, the present invention provides a novel    compound, wherein;-   R³ is selected from Q, C₁₋₆ alkylene-Q, C(O)(CR^(a)R^(a1))_(r)-Q,    C(O)OR^(a1), C(O)NR^(a)R^(a1), C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q, and    S(O)_(p)(CR^(a)R^(a1))_(r)-Q;-   Q, at each occurrence, is independently selected from H, cyclopropyl    substituted with 0–1 R^(d), cyclopentyl substituted with 0–1 R^(d),    cyclohexyl substituted with 0–1 R^(d), phenyl substituted with 0–2    R^(d), and a heteroaryl substituted with 0–3 R^(d), wherein the    heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl,    imidazolyl, and isoxazolyl;-   R⁵ is selected from H, methyl, and ethyl;-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    and (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3); and-   r, at each occurrence, is selected from 0, 1, 2, and 3.    [21] In another preferred embodiment, the present invention provides    a novel compound selected from the group:-   4-[(2-methyl-4-quinolinyl)methoxy]-N-[(2S)-6,8,10-trioxo-7,9-diazaspiro[4.5]dec-2-yl]benzamide;    and-   4-[(2-methyl-4-quinolinyl)methoxy]-N-[(2R)-6,8,10-trioxo-7,9-diazaspiro[4.5]dec-2-yl]benzamide;    or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novelpharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method fortreating an inflammatory disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof the present invention or a pharmaceutically acceptable salt formthereof.

In another embodiment, the present invention provides a novel method oftreating a condition or disease mediated by MMPs, TACE, aggrecanase, ora combination thereof in a mammal, comprising: administering to themammal in need of such treatment a therapeutically effective amount of acompound of the present invention or a pharmaceutically acceptable saltform thereof.

In another embodiment, the present invention provides a novel methodcomprising: administering a compound of the present invention or apharmaceutically acceptable salt form thereof in an amount effective totreat a condition or disease mediated by MMPs, TACE, aggrecanase, or acombination thereof.

In another embodiment, the present invention provides a novel method oftreating a disease or condition, wherein the disease or condition isselected from acute infection, acute phase response, age related maculardegeneration, alcoholic liver disease, allergy, allergic asthma,anorexia, aneurism, aortic aneurism, asthma, atherosclerosis, atopicdermatitis, autoimmune disease, autoimmune hepatitis, Bechet's disease,cachexia, calcium pyrophosphate dihydrate deposition disease,cardiovascular effects, chronic fatigue syndrome, chronic obstructionpulmonary disease, coagulation, congestive heart failure, cornealulceration, Crohn's disease, enteropathic arthropathy, Felty's syndrome,fever, fibromyalgia syndrome, fibrotic disease, gingivitis,glucocorticoid withdrawal syndrome, gout, graft versus host disease,hemorrhage, HIV infection, hyperoxic alveolar injury, infectiousarthritis, inflammation, intermittent hydrarthrosis, Lyme disease,meningitis, multiple sclerosis, myasthenia gravis, mycobacterialinfection, neovascular glaucoma, osteoarthritis, pelvic inflammatorydisease, periodontitis, polymyositis/dermatomyositis, post-ischaemicreperfusion injury, post-radiation asthenia, psoriasis, psoriaticarthritis, pulmonary emphysema, pydoderma gangrenosum, relapsingpolychondritis, Reiter's syndrome, rheumatic fever, rheumatoidarthritis, sarcoidosis, scleroderma, sepsis syndrome, Still's disease,shock, Sjogren's syndrome, skin inflammatory diseases, solid tumorgrowth and tumor invasion by secondary metastases, spondylitis, stroke,systemic lupus erythematosus, ulcerative colitis, uveitis, vasculitis,and Wegener's granulomatosis.

In another embodiment, the present invention provides novel compounds ofthe present invention for use in therapy.

In another embodiment, the present invention provides the use of novelcompounds of the present invention for the manufacture of a medicamentfor the treatment of a condition or disease mediated by MMPs, TACE,aggrecanase, or a combination thereof.

In another embodiment, the present invention provides a method fortreating inflammatory disorders, comprising: administering, to a mammalin need of such treatment, a therapeutically effective amount of one ofthe compounds of the present invention, in combination with one or moreadditional anti-inflammatory agents selected from selective COX-2inhibitors, interleukin-1 antagonists, dihydroorotate synthaseinhibitors, p38 MAP kinase inhibitors, TNF-α inhibitors, TNF-αsequestration agents, and methotrexate.

This invention also encompasses all combinations of preferred aspects ofthe invention noted herein. It is understood that any and allembodiments of the present invention may be taken in conjunction withany other embodiment to describe additional even more preferredembodiments of the present invention. It is also understood that eachand every element of any embodiment is intended to be a separatespecific embodiment. Furthermore, any elements of an embodiment aremeant to be combined with any and all other elements from any of theembodiments to describe additional embodiments.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Geometric isomers of double bonds such as olefins and C═N double bondscan also be present in the compounds described herein, and all suchstable isomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, and racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention.

Preferably, the molecular weight of compounds of the present inventionis less than about 500, 550, 600, 650, 700, 750, 800, 850, or 900 gramsper mole. More preferably, the molecular weight is less than about 850grams per mole. Even more preferably, the molecular weight is less thanabout 750 grams per mole. Still more preferably, the molecular weight isless than about 700 grams per mole.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. When aring system (e.g., carbocyclic or heterocyclic) is said to besubstituted with a carbonyl group or a double bond, it is intended thatthe carbonyl group or double bond be part (i.e., within) of the ring.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

The term “independently selected from”, “independently, at eachoccurrence” or similar language, means that the labeled R substitutiongroup may appear more than once and that each appearance may be adifferent atom or molecule found in the definition of that labeled Rsubstitution group. Thus if the labeled R^(a) substitution group appearfour times in a given permutation of Formula I, then each of thoselabeled R^(a) substitution groups may be a different group falling inthe definition of R^(a). Also, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

It is understood by one skilled in the art that in Formula I, once R²and R³ together with the carbon atom to which they are attached combineto form a ring, R² is not available to form a ring with R⁴. Similarly,once R² and R⁴ together with the carbon atom to which they are attachedcombine to form a ring, R⁴ is not available to form a ring with R⁵.

In cases wherein there are amines on the compounds of this invention,these can be converted to amine N-oxides by treatment with MCPBA and orhydrogen peroxides to afford other compounds of this invention. Thus,all shown amines are considered to cover both the shown amine and itsN-oxide (N→O) derivative.

As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. C₁₋₁₀ alkyl (or alkylene),is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkylgroups. Examples of alkyl include, but are not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, ands-pentyl. “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through an oxygen bridge. C₁₋₁₀ alkoxy, isintended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkoxygroups. Examples of alkoxy include, but are not limited to, methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy,and s-pentoxy. “Cycloalkyl” is intended to include saturated ringgroups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C₃₋₇cycloalkyl, is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. “Alkenyl” or “alkenylene” is intended to include hydrocarbonchains of either a straight or branched configuration and one or moreunsaturated carbon-carbon bonds which may occur in any stable pointalong the chain, such as ethenyl and propenyl. C₂₋₁₀ alkenyl (oralkenylene), is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, andC₁₀ alkenyl groups. “Alkynyl” or “alkynylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more triple carbon-carbon bonds which may occur in any stablepoint along the chain, such as ethynyl and propynyl. C₂₋₁₀ alkynyl (oralkynylene), is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, andC₁₀ alkynyl groups.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane,[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,and tetrahydronaphthyl.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The nitrogen and sulfur heteroatoms may optionally be oxidized.The nitrogen atom may be substituted or unsubstituted (i.e., N or NRwherein R is H or another substituent, if defined). The heterocyclicring may be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure. The heterocyclic ringsdescribed herein may be substituted on carbon or on a nitrogen atom ifthe resulting compound is stable. A nitrogen in the heterocycle mayoptionally be quaternized. It is preferred that when the total number ofS and O atoms in the heterocycle exceeds 1, then these heteroatoms arenot adjacent to one another. It is preferred that the total number of Sand O atoms in the heterocycle is not more than 1. As used herein, theterm “aromatic heterocyclic group” or “heteroaryl” is intended to mean astable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or10-membered bicyclic heterocyclic aromatic ring which consists of carbonatoms and 1, 2, 3, or 4 heterotams independently selected from the groupconsisting of N, O and S. It is to be noted that total number of S and Oatoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl,1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl,1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl,3,4-dihydro-2H-chromen-4-yl, imidazo[1,2-a]pyridinyl,imidazo[1,5-a]pyridinyl, and pyrazolo[1,5-a]pyridinyl. Also included arefused ring and spiro compounds containing, for example, the aboveheterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; and alkali or organic saltsof acidic residues such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of the present invention may be delivered in prodrug form.Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers that release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention or an amount of the combination ofcompounds claimed effective to inhibit a desired metalloprotease in amammal. The combination of compounds is preferably a synergisticcombination. Synergy, as described for example by Chou and Talalay, Adv.Enzyme Regul. 22:27–55 (1984), occurs when the effect (in this case,inhibition of the desired target) of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at suboptimal concentrations of thecompounds. Synergy can be in terms of lower cytotoxicity, increasedanti-inflammatory effect, or some other beneficial effect of thecombination compared with the individual components.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents that are compatible withthe reaction conditions will be readily apparent to one skilled in theart and alternate methods must then be used.

Compounds of formula I, wherein A is C(═O), B is O and L is O, can besynthesized using a variety of literature methods. For example, startingfrom diester 1 and urea (Scheme 1), the pyrimidinetrione 3 can beprepared by treatment with sodium methoxide in methanol (Reddy, D. B. etal. Heterocyclic Chem. 1993, 4, 55), magnesium methoxide generated insitu (Blicke, F. F. et al. J. Am. Chem. Soc. 1941, 63, 2945), orpotassium tert-butoxide in DMSO (Fraser, W. et al. J. Chem. Soc. PerkinTrans. I 1990, 3137). Alternatively, 3 can be synthesized from di-amide2 using diethyl carbonate, sodium hydroxide and ammonia (Shimo, K. etal. J. Org. Chem. 1959, 24, 19).

A series of pyrimidinetriones where U—X—Y—Z group is a phenone can beprepared following a sequence outlined in Scheme 2. TBS protection andreduction of 4-hydroxycinnamic acid 4 provide alcohol 5. Conversion tobromide and coupling with properly functionalized malonate 7 givediester 8. The silyl protecting group can be removed with TBAF and theresultant phenol 9 is functionalized with ClCH₂—Z^(a) (10). Compound 11is converted to pyrimidinetrione following conditions outlined inScheme 1. The olefin moiety in 12 is converted to ketone 13 using amodified Wacker oxidation (Miller, D. G. et al. J. Org. Chem. 1990, 55,2924).

A series of pyrimidinetriones where —U— is an NHC(O) group can beprepared following a sequence outlined in Scheme 3. Malonate diester 7is alkylated to provide disubstituted malonate 14. The olefin group isconverted to aldehyde by ozonolysis and further oxidized to acid withsodium chlorite. Curtius rearrangement in the presence of benzyl alcoholgives Cbz-protected amine 17. After removal of the Cbz group, amine 18is coupled with functionalized acid chloride 19 or acid 20. Diester 21is converted to pyrimidinetrione 22 following conditions outlined inScheme 1.

Alternatively, amine 18 can be prepared by alkylation of malonate 7 withN-bromomethyl succinimide 23 (Scheme 4). The succinyl group can beremoved by treatment with hydrazine to provide amine 18. Conversion of18 to 22 is outlined in Scheme 3.

As another alternative, dimethyl malonate 7 is converted todibenzylamino derivative 25 via Mannich reaction with paraformaldehydeand dibenzylamine (Scheme 5). Debenzylation under hydrogenationconditions yields amine 18. Conversion of 18 to 22 is outlined in Scheme3.

A series of pyrimidinetriones where R¹ and R² combine to form acarbocyclic ring or a cyclic ether can be prepared following a sequenceoutline in Scheme 6. The cyclic acid 26 is either commercially availableor prepared following published procedures (WO 01/70673). Acid 26 isfirst esterified and then treated with LDA and methyl chloroformate toeffect carbometoxylation. Diester 28 is converted to pyrimidinetrione 29following previously described conditions. After removal of the Bocprotecting group, the resultant amine 30 is coupled with acid chloride19 or acid 20 to complete the synthesis of 31.

A series of pyrimidinetriones where R¹ and R⁴ combine to form acarbocyclic ring can be prepared following a sequence outlined in Scheme6a. Acid 26a is first esterified and then treated with LDA and methylchloroformate to effect carbometoxylation. Diester 28a is converted topyrimidinetrione 29a following previously described conditions. Afterremoval of the Boc protecting group, the resultant amine 30a is coupledwith acid chloride 19 or acid 20 to complete the synthesis of 31a.

A series of pyrimidinetriones where R¹ is a functionalized piperazinylgroup can be prepared following a sequence outlined in Scheme 7.Piperazine 33 is alkylated with dimethyl bromomalonate 32 to give 34.Mannich reaction of 34 with peraformaldehyde and dibenzyl amine yields35. The benzyl groups are removed and amine 36 is coupled with acidchloride 19 or acid 20. After conversion of 37 to 38 using previouslydescribed conditions, the Boc group is removed and the piperazine isconverted to tertiary amines by reductive amination, amides by reactionwith anhydrides or acid chlorides, sulfonamides with sulfonyl chlorides,ureas with isocyanates, or carbamates with chloroformates.

A series of pyrimidinetriones where R¹ is a 4-piperidinyl group isprepared following a sequence outlined in Scheme 8. Condensation ofdimethyl malonate 41 with piperidone 42 gives piperidinylmalonate 44after hydrogenation. Alkylation of 44 with N-bromomethyl phthalimideyields 45, which is deprotected, coupled with 19 or 20, and converted to48 following conditions described previously. Removal of Boc group andfunctionalization with R^(d) complete the synthesis of 50.

A series of pyrimidinediones of formula 63 can be prepared following asequence outlined in Scheme 9. After Boc protection of β-alanine,consecutive alkylation with R¹-I and allyl bromide is effected with LDAin the presence of HMPA. Deprotection of Boc group and reaction withp-nitrophenyl chloroformate provide carbamate 57 which is converted tourea 58. Pyrimidinedione formation is effected with a base such ascesium carbonate. Olefin 59 is then converted to acid 61 via consecutiveoxidations and coupled with amine 62 to complete the synthesis.

A series of pyrimidinediones of formula 67 can be synthesized followinga sequence outlined in Scheme 10. Acid 61 is converted to acyl azide 64by formation of mixed anhydride and treatment with sodium azide. Curtiusrearrangement in the presence benzyl alcohol gives Cbz-protected amine65. Deprotection and coupling with acid chloride 19 or acid 20 completethe synthesis of 67.

A series of pyrimidinetriones where R¹ and R² combine to form cyclicamines can be prepared following a sequence outline in Scheme 11. Thecyclic amino ester 68 is prepared following published procedures (WO01/70673). 68 is first protected with Cbz group and then treated withLDA and methyl chloroformate to effect carbometoxylation. Diester 70 isconverted to pyrimidinetrione 71 following previously describedconditions. After removal of the Cbz protecting group, the resultantamine 72 is coupled with acid chloride 19 or acid 20 to provide 73.After removal of the Boc group, the resultant amine is converted totertiary amines by reductive amination, amides by reaction withanhydrides or acid chlorides, sulfonamides with sulfonyl chlorides,ureas with isocyanates, or carbamates with chloroformates.

One isomer of a compound of Formula I may display superior activitycompared with the others. Thus, the following eight stereoisomers (I-Ato I-H) are considered to be a part of the present invention. Eachstereoisomer can be synthesized selectively using the chemistrydescribed in the previous sections, or synthesized as a mixture andseparated at intermediate or final compound stage by HPLC or chiralHPLC.

When required, separation of the racemic material can be achieved byHPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Wilen, S. H. Tables of Resolving Agentsand Optical Resolutions 1972, 308 pp or using enantiomerically pureacids and bases. A chiral compound of Formula I may also be directlysynthesized using a chiral catalyst or a chiral ligand, e.g., Jacobsen,E. Acc. Chem. Res. 2000, 33, 421–431 or using other enantio- anddiastereo-selective reactions and reagents known to one skilled in theart of asymmetric synthesis.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: “1×” foronce, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq”for equivalent or equivalents, “g” for gram or grams, “mg” for milligramor milligrams, “mL” for milliliter or milliliters, “¹H” for proton, “h”for hour or hours, “M” for molar, “min” for minute or minutes, “MHz” formegahertz, “MS” for mass spectroscopy, “NMR” for nuclear magneticresonance spectroscopy, “rt” for room temperature, “tlc” for thin layerchromatography, “v/v” for volume to volume ratio. “α”, “β”, “R” and “S”are stereochemical designations familiar to those skilled in the art.

Example 15-Methyl-5-(3-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-3-oxopropyl)-2,4,6(1H,3H,5H)-pyrimidinetrione

(1a) tert-Butyl-dimethylsilyl chloride (TBSCl) (15.89 g, 2.1 eq) wasadded to a solution of 4-hydroxycinnamic acid (8.24 g, 50 mmol) andimidazole (10.25 g, 3 eq) in DMF (100 mL) at rt. The resulting solutionwas stirred for 48 h. DMF was removed by high-vac rotary evaporator at60° C. The residue was dissolved in ether (150 mL), washed with 5%citric acid (150 mL), water (150 mL) and brine (150 mL). The ethersolution was dried (MgSO₄) and concentrated to give a white solid (15.74g). This TBS ester was used in the next step without furtherpurification.

(1b) To an ether (100 mL) slurry of the ester (15.74 g, 40 mmol) from(1a) at 0° C. was added DIBAL (1M toluene solution, 100 mL, 2.5 eq)dropwise in 1 h. The reaction mixture was stirred at 0° C. for another 1h then quenched by slowly adding Rochelle's solution (100 mL) at 0° C.The mixture was extracted with ether (2×350 mL). The combined etherphase was washed with brine (350 mL), dried (MgSO₄), filtered through ashort bed of celite and concentrated. The crude product was purified byflash column chromatography (15% ethyl acetate-hexane) to yield thedesired alcohol as a colorless oil (4.68 g, 35% for 2 steps). ¹H NMR wasconsistent with literature data (Young, S. D.; Payne, L. S.; Thompson,W. J.; Gaffin, N.; Lyle, T. A.; Britcher, S. F.; Graham, S. L.; Schultz,T. H.; Deana, A. A.; Darke, P. L.; Zugay, J.; Schleif, W. A.; Quintero,J. C.; Emini, E. A.; Anderson, P. S.; Huff, J. R. J. Med. Chem. 1992,35, 1702–1709).

(1c) The alcohol from (1b) (2.24 g, 8.5 mmol) in ether (35 mL) wastreated with PBr₃ (0.88 mL, 1.1 eq) and stirred for 20 min at 0° C.After the reaction was complete, the mixture was poured into saturatedNaHCO₃ (100 mL), diluted with hexanes. The hexane layer was washed withbrine, dried (MgSO₄), filtered through a short bed of silica gel andconcentrated to give the bromide as a brown oil (1.37 g, 49%). ¹H NMRwas consistent with literature data.

(1d) NaH (60% in mineral oil, 0.3 g, 1.8 eq) was added to a THF (20 mL)solution of dimethyl methylmalonate (0.73 g, 1.2 eq) at 0° C. Themixture was stirred for an additional 10 min, then a THF (20 mL)solution of the bromide (1.37 g, 4.19 mmol) from (1c) was added at 0° C.The mixture was stirred at rt overnight, quenched by slowly addingwater, and extracted with ethyl acetate (2×100 mL), dried (MgSO₄),filtered and purified by flash column chromatography (10% ethylacetate-hexane) to yield the unsaturated TBS ether as a colorless oil(0.85 g, 52%). MS Found: (M+H)⁺=393.

(1e) To a THF (1 mL) solution of the unsaturated TBS ether (0.1 g, 0.25mmol) from (1d) was added TBAF (1 M THF solution, 0.5 mL, 2 eq) at rt.After 20 min, TLC (10% ethyl acetate-hexanes) showed the reaction wascomplete. The mixture was concentrated and purified by flash columnchromatography (25% ethyl acetate-hexane) to yield the unsaturatedphenol as a colorless oil (0.071 g, 99%). MS Found: (M+H)⁺=279.

(1f) The unsaturated phenol (71 mg, 0.26 mmol) from (1e) was mixed with4-(chloromethyl)-2-methylquinoline (50 mg, 1 eq) and cesium carbonate(169 mg, 2 eq) in DMF (1 mL) and the mixture stirred at rt overnight.After the reaction was complete, DMF was removed by high-vac rotaryevaporator at 60° C. The residue was purified by flash columnchromatography (40% ethyl acetate-hexane) to yield the unsaturatedquinoline ether as a colorless oil (95 mg, 84%). MS Found: (M+H)⁺=434.

(1g) Magnesium turnings (24 mg, 4.2 eq) were heated in reflux methanol(3 mL) until the metal disappeared. To the resulting white cloudysolution of magnesium methoxide was added urea (40 mg, 2.8 eq) and theunsaturated quinoline ether (105 mg in 0.5 mL CH₂Cl₂, 0.24 mmol) from(1f). The mixture was refluxed for 48 h, concentrated and purified bysilica gel chromatography (75% ethyl acetate-hexane) to give thebarbituric acid as a white solid (19 mg, 19%). MS Found: (M+H)⁺=430.

(1h) According to a literature procedure (Miller, D. G.; Wayner, D. D.M. J. Org. Chem. 1990, 55, 2924–2927), an acetonitrile-water (7:1, 1 mL)solution of Pd(OAc)₂ (0.9 mg, 0.27 eq), benzoquinone (recrystallizedfrom hexanes, 19.4 mg, 12 eq) and HClO₄ (6 μL) was added to theunsaturated barbituric acid (9 mg) from (1g) and stirred at rt for 96 h.TLC (50% ethyl acetate-hexanes) showed only one product formed. Thetitle barbituric acid (6.6 mg, 71%) was obtained by flash columnchromatography (ethyl acetate) as a white solid. MS Found: (M+H)⁺=446.

Example 24-[(2-Methyl-4-quinolinyl)methoxy]-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]benzamide

(2a) A solution of the dimethyl methylmalonate (5.00 g, 34.2 mmol) intetrahydrofuran (50 mL) was added to a suspension of 60 wt % sodiumhydride (2.05 g, 1.5 eq) in tetrahydrofuran (50 mL) dropwise at rt over5 min. The mixture was stirred at rt for 30 min and allyl bromide (5.92mL, 2.0 eq) was added. After stirring at rt for 1 h, the mixture wasquenched with saturated NaHCO₃ (30 mL) and diluted with ethyl acetate(300 mL). The organic phase was separated and washed with water (20 mL),brine (20 mL), dried (MgSO₄) and concentrated in vacuo to provide thedesired ester (7.00 g). This crude material was taken to the next stepwithout purification. MS found: (M+H)⁺=187.

(2b) Ozone was bubbled into a solution of the crude product fromreaction (2a) (3.50 g, 17.1 mmol) in dichloromethane (200 mL) at −78° C.until the solution turned into blue color. Nitrogen was bubbled into themixture until the blue color disappeared. Following addition oftriphenylphosphine (5.38 g, 1.2 eq), the mixture was stirred at rt for 3h, concentrated and purified by silica gel column chromatography (ethylacetate-hexanes, 2:8) to provide the desired aldehyde (2.40 g, 75% fortwo steps). MS found: (M+H)⁺=189.

(2c) A solution of sodium chlorite (1.01 g, 1.5 eq) and potassiumdihydrogenphosphate (1.10 g, 1.5 eq) in water (18 mL) was added to themixture of the product from reaction (2b) (1.00 g, 5.31 mmol),2-methyl-2-butene (8 mL) and tert-butyl alcohol (8 mL) intetrahydrofuran (8 mL) dropwise over 5 min at rt. After stirring at rtfor 30 min, the mixture was adjusted to pH 2–3 with 1 N HCl, dilutedwith ethyl acetate (200 mL), washed with water (2×10 mL), brine (10 mL),dried (MgSO₄) and concentrated in vacuo to provide the desired acid(1.20 g). The crude material was taken to the next step withoutpurification. MS found: (M+H)⁺=205.

(2d) The crude product from reaction (2c) (500 mg, 2.21 mmol) wastreated with triethylamine (0.62 mL, 2.0 eq) and diphenylphosphorylazide (0.57 mL, 1.2 eq) in benzene (10 mL) at rt and the mixture heatedto reflux for 1 h. The mixture was cooled to rt and benzyl alcohol (0.27mL, 1.2 eq) was added. The resulting mixture was heated to reflux for 1h, cooled to rt, quenched with saturated NaHCO₃ (10 mL), diluted withethyl acetate (200 mL), washed with water (2×10 mL), brine (10 mL),dried (MgSO₄) and concentrated in vacuo. Purification of the residue bysilica gel column chromatography (ethyl acetate-hexanes, 2:8) providedthe desired ester (540 mg, 79% for two steps). MS found: (M+H)⁺=310.

(2e) The product from reaction (2d) (500 mg, 1.61 mmol) in methanol (30mL) was treated with 10 wt % palladium on carbon (100 mg) and stirredunder balloon pressure hydrogen for 2 h. The mixture was purged withnitrogen and filtered through a plug of celite. The filter plug waswashed with methanol until free of product. The filtrate was treatedwith 1 N HCl in ether (2 mL) and concentrated to provide the desiredamine as hydrogen chloride salt (340 mg, 100%). MS found: (M+H)⁺=176.

(2f) Saturated NaHCO₃ (10 mL) was added to a vigorously stirred solutionof the product from reaction (2e) (100 mg, 0.472 mmol) and4-[(2-methyl-4-quinolinyl)methoxy]benzoyl chloride (173 mg, 1.05 eq) indichloromethane (10 mL) at rt. After stirring for 10 min, the mixturewas diluted with ethyl acetate (100 mL), washed with water (10 mL),brine (10 mL), dried (MgSO₄) and concentrated in vacuo. Purification ofthe residue by silica gel column chromatography (ethyl acetate-hexanes,7:3) provided the desired amide (200 mg, 94%). MS found: (M+Na)⁺=473.

(2g) In an analogous procedure to reaction (1g), the product fromreaction (2f) (30.0 mg, 0.0666 mmol) was converted to the titlebarbituric acid and purified by silica gel column chromatography(methanol-dichloromethane, 5:95) to provide the barbituric acid (3.0 mg,10%). MS found: (M+H)⁺=447.

Example 34-[(1,1-Dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]benzamidetrifluoroacetate

(3a) To a THF (20 mL) solution of dimethyl methylmalonate (5.5 g, 37mmol) at −10° C. was added NaH (60% in mineral oil, 1.66 g, 1.1 eq). Themixture was stirred for 20 min, then N-bromomethylphthalimide (9.5 g,1.05 eq) was added at 0° C. The mixture was allowed to slowly warm tort, stirred for 3 h, and quenched with water. Following extraction withethyl acetate, the combined ethyl acetate extracts were washed with 1 NHCl and brine, dried (MgSO₄), filtered and concentrated. Purification byflash column chromatography (20% ethyl acetate-hexane) yielded thephthalimide as a white crystalline solid (5.81 g, 51%).

(3b) To a methanol (50 mL) solution of the phthalimide (1.33 g, 4.36mmol) from (3a) was added hydrazine (0.15 mL, 1.1 eq) and the mixturewas stirred at rt for 96 h. The mixture was concentrated and purified byflash column chromatography (6% methanol-methylene chloride) to yieldthe amine as a colorless oil (0.40 g, 53%). The amine was then treatedwith HCl (1 N THF solution) to give the HCl salt as a white solid. MSFound: (M+H)⁺=176.

(3c) Potassium carbonate (4.4 g, 31.9 mmol) and 1,2-dibromoethane (690μL, 8.0 mmol) were added to a solution of 2-aminothiophenol (1.0 g, 8.0mmol) in 20 mL of acetone at rt. The reaction mixture was stirredovernight. The insoluble material was filtered off and the filtrate wasconcentrated in vacuo. The residue was purified on silica gel column toprovide 3,4-dihydro-2H-1,4-benzothiazine (0.8 g, 66%). MS (ES⁺): 152(M+1).

(3d) Potassium carbonate (5.2 g, 37.7 mmol) and methyl4-(bromomethyl)benzoate (2.8 g, 12.6 mmol) were added to a solution of(3c) (1.9 g, 12.6 mmol) in 20 mL of anhydrous DMF. The reaction mixturewas heated to 80° C. overnight. After cooling to rt, the solid wasfiltered off and rinsed with DMF. The filtrate was concentrated in vacuoand the residue was purified on silica gel column to provide methyl4-(2,3-dihydro-4H-1,4-benzothiazin-4-ylmethyl)benzoate (3.02 g, 80%). MS(ES⁺): 300 (M+1).

(3e) A solution of Oxone® (15.5 g, 25.3 mmol) in 30 mL of water wasadded slowly to a solution of (3d) (3.02 g, 10.1 mmol) in 80 mL of MeOH.Upon completion of the reaction, the solution was diluted with ethylacetate, washed with saturated NaHCO₃ and dried over MgSO₄. Afterfiltration and concentration, the residue was purified on silica gelcolumn to provide methyl4-[(1,1-dioxido-2,3-dihydro-4-H-1,4-benzothiazin-4-yl)methyl]benzoate(1.25 g, 37%). MS (AP⁺): 332 (M+1).

(3f) A mixture of the benzoate from reaction (3e) (5.18 g, 15.6 mmol)and sodium hydroxide (1.25 g, 2 eq) in methanol (50 mL) and water (50mL) was heated to reflux for 2 days. Upon completion, the mixture wasneutralized to pH 4 with 1 N HCl and concentrated. The residue wastreated with methanol and filtered. The filtrate was concentrated toprovide the desired acid (4.60 g, 93%). MS (ES⁺): 318 (M+1).

(3g) The HCl salt (52 mg, 0.25 mmol) from (3b) was mixed with the acid(78 mg, 1 eq) from (3f), PyBrop (115 mg, 1 eq), DIPEA (214 μL, 5 eq) andCH₂Cl₂ (2 mL) at rt. After stirring overnight, the material was purifiedby flash column chromatography (50% ethyl acetate-hexanes) to yield theamide as a sticky solid (95 mg, 81%). MS Found: (M+H)⁺=475.

(3h) Magnesium turnings (24 mg, 5 eq) was heated in reflux methanol (3mL) until the metal disappeared. To this white cloudy solution ofmagnesium methoxide was added urea (24 mg, 2 eq) and the amide (95 mg,0.2 mmol) from (3g). The mixture was heated at reflux for 5.5 h and thenconcentrated. The resulting white solid was dissolved in acetonitrile (1mL), water (2 mL) and TFA (0.5 mL) and purified by preparative reversephase HPLC (30–60% CH₃CN-water with 0.1% TFA) to give the titlebarbituric acid (27 mg, 29%). MS Found: (M+H)⁺=471.

Example 44-[(2-Methyl-4-quinolinyl)methyl]-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]benzamidetrifluoroacetate

(4a) 4-Hydroxy-2-methylquinoline (17.4 g, 109 mmol) and phosphorusoxytribromide (47.1 g, 164 mmol) were added to a round-bottom flask. Themixture was heated to 130° C. for several hours. After cooling to rt,the residue was partitioned between saturated Na₂CO₃ and ethyl acetate.The organic layer was separated and the aqueous layer was extracted withethyl acetate (5×300 mL). The combined organic layer was washed with H₂O(2×400 mL) and brine (1×400 mL) and dried over MgSO₄. After filtrationand concentration, the residue was purified on silica gel to provide4-bromo-2-methylquinoline (8.8 g, 36%). MS (AP⁺): 221.8, 223.8 (M+1).

(4b) 4-Bromo-2-methylquinoline from (4a) (1.0 g, 4.5 mmol) was dissolvedin 10 mL of anhydrous THF and the resulting solution was cooled to −78°C. A solution of n-BuLi (3.0 mL, 1.6 M, 4.8 mmol) was added slowly andthe resulting solution was maintained at −78° C. for 5 min. Meanwhile,in another flask methyl 4-formylbenzoate (0.9 g, 5.4 mmol) was dissolvedin 20 mL of anhydrous THF and the resulting solution was cooled to −78°C. before the lithium reagent made above was cannulated. The wholemixture was stirred for 30 min and quenched with MeOH. The solution wasdiluted with ethyl acetate and washed with H₂O and brine. After driedover MgSO₄, the organic solution was filtered and concentrated. Theresidue was purified on silica gel to provide methyl4-[hydroxy(2-methyl-4-quinolinyl)methyl]benzoate (0.9 g, 65%). MS (AP⁺):308 (M+1).

(4c) The benzoate from (4b) (105 mg, 0.34 mmol) was dissolved in 1 mL ofdichloromethane. The solution was cooled to 0° C. and triethylamine (95μL, 0.68 mmol) and MsCl (32 μL, 0.41 mmol) were added. The ice bath wasremoved and the reaction was monitored by TLC until the disappearance ofstarting material. The solution was diluted with ethyl acetate andwashed with H₂O and brine. The organic layer was dried over MgSO₄,filtered, and concentrated. The residue was purified to provide themesylate (130 mg, quantitative yield). MS (AP⁺): 386 (M+1).

(4d) A solution of (4c) (120 mg, 0.31 mmol) in 3 mL of MeOH was added toa suspension of the Pd/C catalyst (60 mg, 10%) in 2 mL of MeOH. Thereaction took place after the flask was purged with H₂. The reaction wasmonitored using TLC until disappearance of the starting material. Afterfiltered, the solution was concentrated and the residue was purified onsilica gel to provide methyl 4-[(2-methyl-4-quinolinyl)methyl]benzoate(90 mg, quantitative yield). MS (AP⁺): 292 (M+1).

(4e) A solution of aqueous NaOH (1N, 35 mL) was added to a solution of(4d) (5.0 g, 17.2 mmol) in 100 mL of MeOH. The reaction mixture washeated to 60° C. until completion of the reaction, monitored by TLC.Upon the completion, one equivalent of aqueous HCl (1 N, 35 mL) wasadded to neutralize the base. The solution was concentrated to drynessand the residue was re-dissolved in MeOH. After filtration, themethanolic solution was concentrated to provide4-[(2-methyl-4-quinolinyl)methyl]benzoic acid (4.8 g, quantitativeyield). MS (ES⁺): 278 (M+1).

(4f) Using a procedure analogous to reaction (3g), the HCl salt (61 mg,0.35 mmol) from (3b) was treated with the acid (96 mg, 1 eq) from (4e)to yield the amide as a white solid (72 mg, 48%). MS Found: (M+H)⁺=435.

(4g) Using a procedure analogous to reaction (3h), the title barbituricacid (21 mg, 38%) was obtained. MS Found: (M+H)⁺=431.

Example 54-[(2-Isopropyl-1H-benzimidazol-1-yl)methyl]-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]benzamidetrifluoroacetate

(5a) Using a procedure analogous to reaction (3g), the HCl salt (70 mg,0.4 mmol) from (3b) was treated with4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoic acid (117 mg, 1 eq)to yield the amide as a white solid (124 mg, 69%). MS Found: (M+H)⁺=452.

(5b) Using a procedure analogous to reaction (3h), the title barbituricacid (35 mg, 37%) was obtained. MS Found: (M+H)⁺=448.

Example 6N-{4-[(2-Methyl-4-quinolinyl)methoxy]phenyl}-2-(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)acetamidetrifluoroacetate

(6a) Using a procedure analogous to reaction (1d), the cinnamyl bromide(4.65 mL, 2 eq) was treated with the anion of dimethyl methylmalonate(2.30 g, 15.7 mmol) and the cinnamyl diester (4 g, 97%) was obtainedafter flash column chromatography (5% ethyl acetate-hexanes). MS Found:(M+H)⁺=263.

(6b) Using a procedure analogous to reaction (1g), the cinnamyl diester(4 g, 15.2 mmol) from (6a) was converted to the cinnamyl barbituric acid(2.9 g, 74%) that was recrystallized from ethyl acetate-hexanes. MSFound: (M−H)⁻=257.

(6c) The cinnamyl barbituric acid (0.675 g, 2.6 mmol) from (6b) wasozonolyzed in methylene chloride-methanol (1:1, 20 mL) solution at −78°C. The reaction was quenched at −78° C. by adding triphenylphosphine(0.72 g, 1.1 eq). The mixture was slowly warmed to rt, concentrated andpurified by flash column chromatography (2–10% methanol-methylenechloride) to give the aldehyde (0.48 g, 100%).

(6d) To a tert-butanol-THF-cis-2-methylbutene (1:1:1, 27 mL) solution ofthe aldehyde (0.66 g, 3.58 mmol) from (6c) was added an aqueous solution(8.25 mL) of NaClO₂ (0.54 g, 1.2 eq) and NaH₂PO₄ (0.45 g, 1.2 eq). Themixture was stirred overnight at rt and then acidified to pH 3 byaddition of 1 N HCl. The mixture was concentrated and dissolved inmethanol-methylene chloride (1:1, 70 mL) solution and filtered. Thefiltrate was concentrated and purified by preparative reverse phase HPLC(0–50% acetonitrile-water with 0.1% TFA) to give the acid (0.63 g, 88%)as a white crystalline solid.

(6e) A mixture of the acid (22 mg, 0.11 eq) from (6d),4-[(2-methyl-4-quinolinyl)methoxy]aniline HCl salt (40 mg, 1 eq),PyBrop(60 mg, 1.1 eq), DIPEA (0.1 mL, 5 eq) and CH₂Cl₂ (2 mL) wasstirred at rt for 4 h. The mixture was concentrated and washed withacetonitrile. The white precipitate was isolated, dissolved in methanol(1 mL), water (1 mL) and TFA (0.5 mL) and purified by preparativereverse phase HPLC (30–60% acetonitrile-water with 0.1% TFA) to give thetitle barbituric acid as a white TFA salt (23 mg, 48%). MS Found:(M+H)⁺=447.

Example 7 tert-Butyl4-{5-[({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)methyl]-2,4,6-trioxohexahydro-5-pyrimidinyl}-1-piperazinecarboxylate

(7a) A mixture of dimethyl bromomalonate (34.2 g, 146 mmol), tert-butyl1-piperazinecarboxylate (27.2 g, 146 mmol) and potassium carbonate (20g, 146 mmol) in acetonitrile (300 mL) was stirred at rt overnight. Uponremoval of solvent, the residue was treated with water (100 mL) andextracted with ethyl acetate (2×200 mL). The combined extracts werewashed with brine (100 mL), dried (Na₂SO₄), filtered, and concentrated.Silica gel chromatography (25% ethyl acetate/hexane) provided thedesired product (39.4 g, 85%). MS found: (M+H)⁺=317.

(7b) A mixture of the malonate (15.5 g, 54 mmol) from reaction (7a),paraformaldehyde (16.2 g, 540 mmol) and dibenzylamine (53.3 g, 270 mmol)was heated at 90° C. overnight. The reaction mixture was allowed to coolto rt, dissolved in dichloromethane, and purified by silica gelchromatography (20% ethyl acetate/hexane) to provide the desired product(11 g, 43%). MS found: (M+H)⁺=526.

(7c) A mixture of the dibenzylamine (12.1 g, 23.0 mmol) from reaction(7b), triethylamine (2.3 g, 23.0 mmol) and Pd(OH)₂/C (3.2 g) in methanol(460 mL) was hydrogenated at 50–55 psi overnight. The catalyst wasremoved by filtration. The filtrate was concentrated to provide thedesired amine (7.2 g, 91%). MS found: (M+H)⁺=346.

(7d) A mixture of the amine (7.0 g, 20.3 mmol) from reaction (7c),4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid (6.2 g, 21.3 mmol), BOPreagent (10.8 g, 24.3 mmol) and N,N-diisopropylethylamine (9.2 g, 70.9mmol) in DMF (200 mL) was stirred at rt for 3 h. The mixture was cooledto 0° C., partitioned between aqueous NaHCO₃ and ethyl acetate (200 mLeach). The aqueous layer was further extracted with ethyl acetate (2×250mL). The combined organic layers were washed with brine, dried (Na₂SO₄)and concentrated. Silica gel column chromatography (20% ethylacetate/hexane) yielded the desired amide (11.9 g, 94%). MS found:(M+H)⁺=621.

(7e) Magnesium turnings (773 mg, 32.2 mmol) in methanol (30 mL) wasrefluxed under nitrogen until all the magnesium was dissolved (1–2 h).After the resulting white slurry was allowed to cool to rt, a solutionof the amide (2 g, 3.2 mmol) from reaction (7d) and urea (387 mg, 6.4mmol) in methanol (20 mL) was added. The mixture was maintained atreflux overnight, cooled to 0° C., and quenched with 1 N hydrochloricacid (64 mL) to pH 5. After separation of two phases by filtration, thesolid was heated to reflux in methanol to recover additional product andfiltered. The combined filtrate was extracted with ethyl acetate (2×200mL). The combined extracts were washed with brine, dried (Na₂SO₄) andconcentrated. Silica gel chromatography (7% then 10%methanol/dichloromethane) provided the desired barbituric acid (600 mg,30%). MS found: (M+H)⁺=617.

Example 84-[(2-Methyl-4-quinolinyl)methoxy]-N-{[2,4,6-trioxo-5-(1-piperazinyl)hexahydro-5-pyrimidinyl]methyl}benzamidetris(trifluoroacetate)

To a mixture of the barbituric acid (0.32 g, 0.52 mmol) from reaction(7e) in dichloromethane (30 mL) was added trifluoroacetic acid (5 mL).The resulting solution was stirred at rt for 1.5 h. Upon removal ofsolvent, the residue was purified by reverse phase HPLC (10–80%acetonitrile/water) to provide the desired product (0.18 g, 41%). MSfound: (M+H)⁺=517.

Example 9N-{[5-(4-Methyl-1-piperazinyl)-2,4,6-trioxohexahydro-5-pyrimidinyl]methyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamidetris(trifluoroacetate)

To a mixture of the amine (25 mg, 0.029 mmol) from reaction (8) andformaldehyde (37% aqueous solution, 3.3 μL, 1.5 eq) in dichloromethanewere added N,N-diisopropylethylamine (15 μL, 3 eq) and sodiumtriacetoxyborohydride (9.2 mg, 1.5 eq). After stirring at rt for 2 h,the reaction mixture was quenched with aqueous NaHCO₃. Upon removal ofdichloromethane, the aqueous residue was treated with methanol to aclear solution and purified by reverse phase HPLC (10–80%acetonitrile/water) to provide the desired N-methylated product (6 mg,24%). MS found: (M+H)⁺=531.

Example 104-[(2-Methyl-4-quinolinyl)methoxy]-N-({2,4,6-trioxo-5-[4-(2-propynyl)-1-piperazinyl]hexahydro-5-pyrimidinyl}methyl)benzamidetris(trifluoroacetate)

To a mixture of the amine (25 mg, 0.029 mmol) from reaction (8) andpropargyl bromide (4.2 μl, 1.3 eq) in dichloromethane was addedtriethylamine (20 μl, 5 eq). After stirring at rt for 2 h, the reactionmixture was quenched with water. Upon removal of dichloromethane, theaqueous residue was treated with methanol to a clear solution andpurified by reverse phase HPLC (10–80% acetonitrile/water) to providethe desired N-propargyl product (3.6 mg, 14%). MS found: (M+H)⁺=555.

Example 114-[(2-Methyl-4-quinolinyl)methoxy]-N-({5-[4-(methylsulfonyl)-1-piperazinyl]-2,4,6-trioxohexahydro-5-pyrimidinyl}methyl)benzamidebis(trifluoroacetate)

Following procedures similar to that used for reaction (10), the aminefrom reaction (8) was converted to N-methylsulfonamide withmethanesulfonyl chloride (6 μL, 1.3 eq). Purification using reversephase HPLC (10–80% acetonitrile/water) provided the desired product (18mg, 38%). MS found: (M+H)⁺=595.

Example 12 tert-Butyl5-[({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)methyl]-2,4,6-trioxohexahydro-5-pyrimidinylcarbamatetrifluoroacetate

(12a) A mixture of dimethyl aminomalonate hydrochloride (10 g, 54.5mmol), di-tert-butyl dicarbonate (12 g, 1.02 eq) and triethylamine (19mL, 2.5 eq) in dichloromethane (200 mL) was stirred overnight. Thereaction was quenched with water/brine (1:1, 100 mL). The organic layerwas separated, dried (MgSO₄), concentrated and purified by silica gelchromatography (40% ethyl acetate/hexane) to provide the desireddimethyl (Boc-amino)malonate (11.9 g, 88%). MS found: (M+H)⁺=270.

(12b) To a solution of the malonate (1.0 g, 4.0 mmol) from reaction(12a) in N,N-dimethylformamide (8 mL) was added at 0° C. sodium hydride(60% dispersion in mineral oil, 0.34 g, 2.1 eq). After 20 min,N-(bromomethyl)phthalimide (1.0 g, 1.04 eq) was added. The reactionmixture was stirred at 0° C. for 1 h before quenched with aqueousammonium chloride, and extracted with ethyl acetate. The extracts werewashed with brine, dried (MgSO₄), concentrated and purified by silicagel chromatography (20% then 40% ethyl acetate/hexane) to provide thedesired alkylated product (0.9 g, 55%). MS found: (M+H)⁺=407.

(12c) A mixture of the product from reaction (12b) (0.8 g, 2.0 mmol) andhydrazine (0.068 mL, 1.1 eq) in methanol (20 mL) was stirred at rtovernight, then refluxed for 5 h. The reaction mixture was allowed tocool to rt. The white precipitate was filtered off. The filtrate wasconcentrated and purified by silica gel chromatography (2.5% then 5%methanol/dichloromethane) to provide the desired free amine (0.16 g,30%). MS found: (M+H)⁺=277.

(12d) A mixture of the amine (0.15 g, 0.54 mmol) from reaction (12c),4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid (0.16 g, 1.02 eq), BOPreagent (0.26 g, 1.1 eq) and N,N-diisopropylethylamine (0.19 mL, 2 eq)in DMF (4 mL) was stirred at rt for 2 h. The mixture was quenched withaqueous NaHCO₃, extracted with ethyl acetate. The extracts were washedwith brine, dried (MgSO₄) and concentrated to provide the crude productas a solid. Recrystallization from ethyl acetate/hexane yielded thedesired amide (0.21 g, 70%). MS found: (M+H)⁺=552.

(12e) Magnesium turnings (76.8 mg, 3.2 mmol) in methanol (3 mL) wererefluxed under nitrogen until all the magnesium were dissolved (1–2 h).The resulting white slurry was allowed to cool to rt. To the mixturewere added urea (38.7 mg, 2 eq) and a solution of the amide (176 mg,0.32 mmol) from reaction (12d) in methanol (2 mL). The mixture wasrefluxed for 3 h, allowed to cool to rt, and quenched with 1 Nhydrochloric acid (5 mL) to pH 5–6. The mixture was then extracted with10% methanol/dichloromethane (3×20 mL). The combined extracts wereconcentrated. Purification using reverse phase HPLC (10–80%acetonitrile/water) provided the acyclic precursor (10 mg). MS found:(M+H)⁺=580.

(12f) The product from reaction (12e) (10 mg, 0.017 mmol) in DMSO (1 mL)was treated with Cs₂CO₃ (28 mg, 5 eq) at rt overnight. Purificationusing reverse phase HPLC (10–80% acetonitrile/water) provided thedesired product (2 mg). MS found: (M+H)⁺=548.

Example 134-[(2-Methyl-4-quinolinyl)methoxy]-N-(1,3,5-trioxo-2,4-diazaspiro[5.5]undec-7-yl)benzamidetrifluoroacetate

(13a) To a methylene chloride-methanol (1:1, 10 mL) solution ofcis-2-(tert-butoxycarbonylamino)-cyclohexanecarboxylic acid (1 g, 4.11mmol) was added TMSCHN₂ (2 M hexane solution, 2.7 mL, 1.3 eq) at rt. Themixture was stirred for 30 min, then concentrated to yield the methylester (0.94 g, 94%). MS Found: (M+H)⁺=258.

(13b) To a THF (10 mL) solution of diisopropylamine (0.68 mL, 2.5 eq) at−78° C. was added butyllithium (1.6 M hexane solution, 3 mL, 2.5 eq).The mixture was stirred at −78° C. for 45 min. The methyl ester (500 mg,1.94 mmol) from (13a) in THF (2 mL) was added and stirred at the sametemperature for 30 min. Finally, methyl chloroformate (0.17 mL, 1.1 eq)was added and the reaction temperature was allowed to slowly warm to rt.The mixture was quenched with saturated NaHCO₃ and ethyl acetate. Theorganic layer was washed with water and brine, dried (MgSO₄), filteredand purified by flash column chromatography (15% ethyl acetate-hexane)to yield the diester (319 mg, 52%). MS Found: (M+H)⁺=316.

(13c) Magnesium turnings (42 mg, 3 eq) was heated in reflux methanol (5mL) until the metal disappeared. To this white cloudy solution ofmagnesium methoxide was added urea (70 mg, 2 eq) and the diester (184mg, 0.59 mmol) from (13b). The mixture was refluxed for 48 h. Theresidue was quenched with 1 N HCl (3 mL), extracted with ethyl acetate(2×15 mL). The organic layer was washed with water (5 mL), dried(MgSO₄), filtered and purified by flash column chromatography (50% ethylacetate-hexane) to yield the N-Boc barbituric acid (74 mg, 41%). MSFound: (M−H)⁻=310.

(13d) To a methylene chloride (3 mL) solution of the N-Boc barbituricacid (70 mg, 0.22 mmol) from (13c) was added TFA (3 mL) at rt. Thesolution was stirred for 1 h then concentrated to give the TFA salt ofthe amino barbituric acid (90 mg). MS Found: (M+H)⁺=212.

(13e) A mixture of the amino barbituric acid (73 mg, 0.22 mmol) from(13d), 4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid (73 mg, 1.1 eq),BOP (119 mg, 1.2 eq), DIPEA (0.159 mL, 4 eq) and DMF (4 mL) was stirredat rt for 1 h then quenched by adding saturated NaHCO₃ (3 mL). Themixture was extracted with ethyl acetate (2×15 mL), dried (MgSO₄),concentrated and purified by preparative HPLC (20–45% acetonitrile-waterwith 0.1% TFA) to give the title barbituric acid as a white TFA salt (20mg, 15%). MS Found: (M+H)⁺=487.

Example 144-[(2-Methyl-4-quinolinyl)methoxy]-N-(6,8,10-trioxo-7,9-diazaspiro[4.5]dec-1-yl)benzamidetrifluoroacetate

(14a) Using procedures analogous to reaction (13a),cis-2-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2 g, 8.7mmol) was converted the methyl ester (1.60 g, 75%).

(14b) Using procedures analogous to reaction (13b), the methyl ester(500 mg, 2.06 mmol) from (14a) was converted to the diester (450 mg,72%). MS Found: (M+H)⁺=302.

(14c) Using procedures analogous to reaction (13c), the diester (100 mg,0.33 mmol) from (14b) was converted to the N-Boc barbituric acid (30 mg,30%). MS Found: (M−H)⁻=296.

(14d) Using procedures analogous to reaction (13d), the N-Boc barbituricacid (30 mg, 0.1 mmol) from (14c) was converted to the amino barbituricacid (35 mg, 100%). MS Found: (M+H)⁺=198.

(14e) Using procedures analogous to reaction (13e), the title barbituricacid was obtained as a white TFA salt (8 mg, 18%). MS Found: (M+H)⁺=473.

Example 154-[(2-Methyl-4-quinolinyl)methoxy]-N-[(2S)-6,8,10-trioxo-7,9-diazaspiro[4.5]dec-2-yl]benzamidetrifluoroacetate

(15a) Using procedures analogous to reaction (13a), the(1S,3R)-N-Boc-1-amino-cyclopentane-3-carboxylic acid (0.52 g, 2.26 mmol)was converted to the methyl ester (0.53 g).

(15b) Using procedures analogous to reaction (13b), the methyl ester(340 mg, 1.4 mmol) from (15a) was converted to the diester (211 mg,50%).

(15c) Using procedures analogous to reaction (13c), the diester (105 mg,0.35 mmol) from (15b) was converted to the N-Boc barbituric acid (11 mg,11%).

(15d) Using procedures analogous to reaction (13d), the N-Boc barbituricacid (11 mg, 0.037 mmol) from (15c) was converted to the aminobarbituric acid. MS Found: (M+H)⁺=198.

(15e) Using procedures analogous to reaction (13e), the amino barbituricacid from (15d) was converted to the title barbituric acid as a whiteTFA salt (8 mg, 48%). MS Found: (M+H)⁺=473.

Example 164-[(2-Methyl-4-quinolinyl)methoxy]-N-[(2R)-6,8,10-trioxo-7,9-diazaspiro[4.5]dec-2-yl]benzamidetrifluoroacetate

(16a) Using procedures analogous to reaction (13a), the(1R,3S)-N-Boc-1-amino-cyclopentane-3-carboxylic acid (0.5 g, 2.18 mmol)was converted to the methyl ester as a white needle crystal (0.51 g,96%). MS Found: (M+H)⁺=244.

(16b) Using procedures analogous to reaction (13b), the methyl ester(510 mg, 2.1 mmol) from (16a) in THF (2 mL) was converted to the diester(104 mg, 17%). MS Found: (M+H)⁺=302.

(16c) Using procedures analogous to reaction (13c), the diester (104 mg,0.35 mmol) from (16b) was converted to the N-Boc barbituric acid (82 mg,81%). MS Found: (M-Boc)⁺=198.

(16d) Using procedures analogous to reaction (13d), the N-Boc barbituricacid (48 mg, 0.16 mmol) from (16c) was converted to the amino barbituricacid. MS Found: (M+H)⁺=198.

(16e) Using procedures analogous to reaction (13e), the amino barbituricacid from (16d) was converted to the title barbituric acid as a whiteTFA salt (21 mg, 30%). MS Found: (M+H)⁺=473.

Example 17N-[(5-Methyl-2,4-dioxohexahydro-5-pyrimidinyl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamidetrifluoroacetate

(17a) A solution of N-(tert-butoxycarbonyl)-β-analine methyl ester (2.50g, 12.3 mmol)and hexamethylphosphoramide (21.4 mL, 10 eq) intetrahydrofuran (50 mL) was added dropwise to a solution of lithiumdiisopropylamide (27.1 mmol, 2.2 eq) in tetrahydrofuran (100 mL) at −78°C. over 10 min. After 30 min at −78° C., iodomethane (0.92 mL, 1.2 eq)was added and the mixture was stirred at 0° C. for 1 h. Saturated NaHCO₃(10 mL) and ethyl acetate (300 mL) were added. The mixture was washedwith water (2×20 mL), brine (20 mL), dried (MgSO₄) and concentrated invacuo. Purification of the residue by silica gel column chromatography(ethyl acetate-hexanes, 2:8) yielded the desired ester (1.40 g, 53%). MSfound: (M+H)⁺=218.

(17b) Using a procedure analogous to reaction (17a), the product fromreaction (17a) (1.40 g, 6.44 mmol) was reacted with allyl bromide (0.72mL, 1.3 eq) to provide the desired ester (1.20 g, 72%). MS found:(M+H)⁺=258.

(17c) The product from reaction (17b) (1.10 g, 4.27 mmol) was treatedwith trifluoacetic acid (5.0 mL) in dichloromethane (5.0 mL) at rt. Themixture was stirred at rt for 1 h and concentrated in vacuo to providethe desired amine (1.16 g, 100%). MS found: (M+H)⁺=158.

(17d) The product from reaction (17c) (1.16 g, 4.27 mmol) was treatedwith N,N-diisopropylethylamine (2.23 mL, 3.0 eq) and 4-nitrophenylchloroformate (947 mg, 1.1 eq) in dichloromethane (50 mL) at rt. After 1h at rt, saturated NaHCO₃ (10 mL) and ethyl acetate (200 mL) were added.The mixture was washed with water (2×10 mL), brine (10 mL), dried(MgSO₄) and concentrated in vacuo. Purification by silica gel columnchromatography (ethyl acetate-hexanes, 2:8) yielded the desired compound(1.04 g, 76%). MS found: (M+H)⁺=323.

(17e) Ammonia gas was bubbled into a solution of the product fromreaction (17d) (1.00 g, 3.10 mmol) in acetonitrile (20 mL) at rt for 5min. The mixture was stirred at rt for 1 h and concentrated in vacuo.The residue was dissolved in DMSO (10 mL) and treated with cesiumcarbonate (3.03 g, 3.0 eq). After 24 h at rt, saturated NaHCO₃ (10 mL)and ethyl acetate (300 mL) were added. The mixture was washed with water(2×20 mL), brine (20 mL), dried (MgSO₄) and concentrated in vacuo.Purification of the residue by crystallization (ethyl acetate-hexanes)yielded the desired pyrimidinedione (350 mg, 676). MS found:(M+CH₃CN+H)⁺=210.

(17f) Ozone was bubbled into a solution of the product from reaction(17e) (320 mg, 1.90 mmol) in dichloromethane (10 mL) and methanol (10mL) at −78° C. until the solution turned into blue color. The mixturewas bubbled with nitrogen until the blue color disappeared. Afteraddition of triphenylphosphine (600 mg, 1.2 eq), the mixture was warmedto rt, stirred for 3 h, and concentrated in vacuo. Purification bysilica gel column chromatography (methanol-dichloromethane, 1:9)provided the desired aldehyde (270 mg, 84%). MS found: (M+CH₃CN+H)⁺=212.

(17g) A solution of sodium chlorite (224 mg, 1.5 eq) and potassiumdihydrogenphosphate (244 mg, 1.5 eq) in water (6.0 mL) was added to amixture of the product from reaction (17f) (200 mg, 1.18 mmol),2-methyl-2-butene (3.0 mL) and tert-butyl alcohol (3.0 mL) intetrahydrofuran (3.0 mL) at rt. After 30 min at rt, the solution wasadjusted pH 2–3 with 1 N HCl. After removal of solvent in vacuo, theresidue was treated with methanol (50 mL), heated to 50° C. for 1 h, andcooled to rt. After removal of precipitate by filtration, the filtratewas concentrated in vacuo to provide the desired acid (300 mg). Thiscrude material was taken to the next step without further purification.MS found: (M+CH₃CN+H)⁺=228.

(17h) Isobutyl chloroformate (80.6 mg, 2.0 eq) was added to a mixture ofthe product from reaction (17g) (75 mg, 0.295 mmol) and triethylamine(0.12 mL, 3.0 eq) in tetrahydrofuran (6.0 mL) at 0° C. After 30 min at0° C., a solution of sodium azide (450 mg, 20 eq) in water (3.0 mL) wasadded and the resultant mixture was stirred at 0° C. for 1 h. Followingaddition of ethyl acetate (100 mL), the mixture was washed with water(10 mL), brine (10 mL), dried (MgSO₄) and concentrated in vacuo. The dryresidue was dissolved in benzene (10 mL), heated to reflux for 1 h, andcooled to rt. Benzyl alcohol (63.8 mg, 2.0 eq) was added. The mixturewas heated to reflux for 1 h,. cooled to rt, and concentrated in vacuo.Purification of the residue by silica gel column chromatography(methanol-dichloromethane, 5:95) provided the desired compound (14 mg,16% for two steps). MS found: (M+H)⁺=292.

(17i) Palladium hydroxide on carbon (5.0 mg, 20 wt %, 0.3 eq) was addedto the product from reaction (17h) (14 mg, 0.048 mmol) in methanol (5.0mL). The mixture was stirred under a balloon of hydrogen for 2 h, purgedwith nitrogen, and filtered through a plug of celite. The filter cakewas washed with methanol until free of product. The filtrate wasconcentrated to provide the desired amine (8.0 mg, 100%). MS found:(M+CH₃CN+H)⁺=199.

(17j) N,N-diisopropylethylamine (0.02 mL, 2.0 eq) and BOP reagent (22.0mg, 1.0 eq) were added to a solution of the amine from reaction (17i)(8.0 mg, 0.048 mmol) and 4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid(14.0 mg, 1.0 eq) in N,N-dimethylformamide (2.0 mL) at rt. After 1 h atrt, saturated NaHCO₃ (5 mL) and ethyl acetate (60 mL) were added. Themixture was washed with water (2×5 mL), brine (5 mL), dried (MgSO₄) andconcentrated in vacuo. Purification of the residue by silica gel columnchromatography (methanol-dichloromethane, 5:95) provided the titlecompound, which was converted to the TFA salt by addition of TFA indichloromethane (13.0 mg, 50%). MS found: (M+H)⁺=433.

Example 182-(5-Methyl-2,4-dioxohexahydro-5-pyrimidinyl)-N-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetamidetrifluoroacetate

Using a procedure analogous to reaction (17j), the crude product fromreaction (17g) (60 mg, 0.118 mmol) was treated with4-[(2-methyl-4-quinolinyl)methoxy]aniline dihydrochloride (40.0 mg, 1.0eq) to provide the title compound (20.0 mg, 31%). MS found: (M+H)⁺=433.

Example 19N-[(5-Ethyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide

(19a–c) Following procedures analogous to that used in reactions (12b),(12c), and (12d), diethyl ethylmalonate was converted to desired amide(0.73 g, 31% for 3 steps). MS found: (M+H)⁺=493.

(19d) To a solution of the product from reaction (19c) (0.40 g, 0.8mmol) and urea (0.24 g, 5 eq) in DMSO (2 mL) was added dropwise asolution of potassium tert-butoxide (1.0 M in THF, 1.6 mL, 2 eq). Themixture was stirred at rt overnight and quenched with aqueous ammoniumchloride. The mixture was then extracted with ethyl acetate/methanol(10:1) until no more product in the aqueous phase as judged by TLCanalysis. The combined extracts were concentrated, and purified bysilica gel chromatography (5% then 10% methanol/dichloromethane) toprovide the title compound (0.20 g, 54%). MS found: (M+H)⁺=461.

Example 20N-{[5-(4-Benzyl-1-piperazinyl)-2,4,6-trioxohexahydro-5-pyrimidinyl]methyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamidetris(trifluoroacetate)

Following a procedure analogous to that used in reaction (9), thematerial from example 8 was reacted with benzaldehyde for 2 days toprovide the title compound (18 mg, 62%). MS found: (M+H)⁺=607.5.

Example 21N-[(5-Isopropyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide

(21a–d) Following procedures analogous to that used in reaction (19a–d),the title compound was obtained (80 mg, 20% for 4 steps). MS found:(M+H)⁺=475.

Example 226-[(2-Methyl-4-quinolinyl)methoxy]-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]-2-naphthamidetrifluoroacetate

(22a) Using a procedure analogous to reaction (3g), the amine (50 mg,0.29 mmol) from (3b) was treated with 6-hydroxy-2-naphthoic acid (54 mg,1 eq) to yield the amide (98 mg, 100%). MS Found: (M+H)⁺=346.

(22b) The amide (98 mg, 0.29 mmol) from (22a) was mixed with4-(chloromethyl)-2-methylquinoline (55 mg, 1 eq) and cesium carbonate(279 mg, 3 eq) in DMF (1 mL) and stirred at rt overnight. The crudemixture was concentrated by a high-vac rotary evaporator at 60° C. andpurified by flash column chromatography (ethyl acetate) to give theether product (92 mg, 64%). MS Found: (M+H)⁺=501.

(22c) In an analogous procedure to (1g) the product from reaction (22b)(92 mg, 0.18 mmol) was reacted with urea and purified by reverse phaseHPLC (25–55% acetonitrile-water with 0.1% TFA) to provide the titlebarbituric acid (14.4 mg, 16%) MS found: (M+H)⁺═=497.

Example 23N-{[5-(4-Isopropyl-1-piperazinyl)-2,4,6-trioxohexahydro-5-pyrimidinyl]methyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamidetris(trifluoroacetate)

Following a procedure analogous to that used in reaction (9), thematerial from example 8 was reacted with acetone for 7 days to providethe title compound (13.7 mg, 52.7%). MS found: (M+H)⁺=559.6.

Example 24N-{[5-(4-Acetyl-1-piperazinyl)-2,4,6-trioxohexahydro-5-pyrimidinyl]methyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamidebis(trifluoroacetate)

Following a procedure analogous to that used in reaction (10), thematerial from example 8 was reacted with acetyl chloride to provide thetitle compound (7 mg, 31%). MS found: (M+H)⁺=559.5.

Example 254-[(2-Methyl-4-quinolinyl)methoxy]-N-({2,4,6-trioxo-5-[4-(3-pyridinylcarbonyl)-1-piperazinyl]hexahydro-5-pyrimidinyl}methyl)benzamide

Following a procedure analogous to that used in reaction (10), thematerial from example 8 was reacted with nicotinoyl chloride overnightto provide the title compound (13 mg, 85%). MS found: (M+H)⁺=622.5.

Example 26N-[(5-Benzyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamidetrifluoroacetate

(26a–d) Following procedures analogous to that used in reactions(19a–d), the title compound was obtained (22 mg, 3.6% for 4 steps). MSfound: (M+H)⁺=523.

Example 273-(2-Methyl-4-quinolinyl)-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]benzamidetrifluoroacetate

(27a) Diisopropylethylamine (5 mL, 3 eq) was added to4-hydroxy-2-methylquinoline and N-phenyl-bis(trifluoromethanesulfonimide) (3.43 g, 1 eq) in DMF (10 mL) at rt and the mixture stirredovernight. The crude material was concentrated by a high-vac rotaryevaporator at 60° C. and purified by flash column chromatography (10%ethyl acetate-hexanes) to give the triflate (2.07 g, 74%). MS Found:(M+H)⁺=292.

(27b) To a degassed solution of the triflate (1.49 g, 5.11 mmol) from(27a), 3-(methoxycarbonyl)phenylboronic acid (0.92 g, 1 eq), aqpotassium carbonate (2.65 M, 3.8 mL, 2 eq) and lithium chloride (0.43 g,2 eq) in ethanol (15 mL) and toluene (30 mL), was addedtetrakis(triphenylphosphine)palladium (0.59 g, 0.1 eq) at rt. Themixture was stirred at 80° C. overnight. Water (50 mL) was added to theresulting black solution. The mixture was extracted with ethyl acetate(2×100 mL), washed with water, dried over MgSO₄ and concentrated. Theresidue was purified by flash column chromatography (20% ethylacetate-hexanes) to give the biaryl product (1.07 g, 75%). MS found:(M+H)⁺=278.

(27c) To a methanol (10 mL) solution of the biaryl product (1.07 g, 3.86mmol) from step (27b) was added aq lithium hydroxide (1 N, 5 mL) and themixture was stirred at 60° C. overnight. The crude mixture wasconcentrated by a high-vac rotary evaporator at 60° C. The resultingwhite powder was washed with methanol-chloroform (5%, 100 mL) andfiltered. The filtrate was concentrated to give the acid as a whitesolid. This crude acid was used in the next step without furtherpurification. MS found: (M+H)⁺=264.

(27d) The amine (67 mg, 1 eq) from (3b) and the acid (99 mg, 0.38 mmol,1 eq) from (27c) were mixed with HATU (295 mg, 1 eq) and DIPEA (655 μL,10 eq) in DMF (2 mL) at rt and the mixture stirred overnight. Followingaddition of water, the mixture was extracted with methylene chloride andpurified by flash column chromatography (ethyl acetate) to yield theamide (136 mg, 86%). MS Found: (M+H)⁺=421.

(27e) In an analogous procedure to (1g), the product from reaction (27d)(136 mg, 0.32 mmol) was reacted with urea and purified by reverse phaseHPLC (25–55% acetonitrile-water with 0.1% TFA) to provide the titlebarbituric acid (2.2 mg, 2%). MS found: (M+H)⁺=417.

Example 28 tert-Butyl4-{5-[({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)methyl]-2,4,6-trioxohexahydro-5-pyrimidinyl}-1-piperidinecarboxylatetrifluoroacetate

(28a) Titanium tetrachloride (22 mL, 0.2 mol) was added dropwise over 30min to a mixture of tetrahydrofuran (400 mL) and carbon tetrachloride(50 mL) at −10° C. To the resulting yellow slurry were added dimethylmalonate (11.5 mL, 0.10 mol), and a solution of tert-butyl4-oxo-1-piperidine carboxylate (20 g, 0.10 mol) in THF (50 mL). Thenpyridine (35 mL) was added dropwise over 30 min. After 30 min at −10°C., the mixture was stirred at ambient temperature overnight. To theresulting slurry was added water (200 mL) and ethyl acetate (200 mL).The organic layer was separated, washed with brine, dried (MgSO₄) andconcentrated in vacuo. Purification using silica gel chromatography (30%ethyl acetate/hexane) provided the desired product with minor impurity(0.81 g), which was used in the next step without further purification.MS found: (M+H)⁺=314.

(28b) The product from reaction (28a) (0.72 g, 2.3 mmol) in methanol (20mL) was treated with 10 wt % palladium on carbon (0.15 g) and themixture stirred under balloon pressure hydrogen for 5 h. The mixture waspurged with nitrogen, and filtered to remove the catalyst. The filtratewas concentrated to provide the desired product (0.71 mg, 98%). MSfound: (M+Na)⁺=338.

(29c–f) Following procedures analogous to that used in reactions(12b–d), and (13c) except that 10 eq of magnesium turnings were used inreaction (29f), the title compound was obtained (0.10 g, 14.9% for 4steps). MS found: (M+H)⁺=616.4.

Example 294-[(2-Methyl-4-quinolinyl)methoxy]-N-{[2,4,6-trioxo-5-(4-piperidinyl)hexahydro-5-pyrimidinyl]methyl}benzamidebis(trifluoroacetate)

Following a procedure analogous to that used in reaction (8), thematerial from Example 28 was converted to the title compound (24 mg,94%). MS found: (M+H)⁺=516.4.

Example 30N-({5-[1-(2,2-Dimethylpropanoyl)-4-piperidinyl]-2,4,6-trioxohexahydro-5-pyrimidinyl}methyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide

Following a procedure analogous to that used in reaction (10), thematerial from Example 8 was reacted with trimethylacetyl chloride for 5days to provide the title compound (10.5 mg, 70%). MS found:(M+H)⁺=601.4.

Example 31N-(5-Methyl-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl)-4-phenoxy-benzamide

(31a) Using a procedure analogous to reaction (3g), the HCl salt (104mg, 0.6 mmol) from (3b) was treated with 4-phenoxybenzoic acid (127 mg,1 eq) to yield the amide as a white solid (146 mg, 66%). MS Found:(M+H)⁺=372.

(31b) Using a procedure analogous to reaction (3h), the title barbituricacid (20 mg, 15%) was obtained. MS Found: (M−H)⁻=366.

Example 32 Biphenyl-4-carboxylic acid[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]amidetrifluoroacetate

(32a) Using a procedure analogous to reaction (3g), the HCl salt (122mg, 0.7 mmol) from (3b) was treated with biphenyl-4-carboxylic acid (138mg, 1 eq) to yield the amide as a white solid (98 mg, 40%).

(32b) Using a procedure analogous to reaction (3h), the title barbituricacid (4 mg, 4%) was obtained. MS Found: (M−H)⁻=350.

Example 334-[(2-Methyl-4-quinolinyl)methoxy]-N-[(5-methyl-2,4,6-trioxohexahydro-5-pyrimidinyl)-(4-pyridinyl)methyl]benzamidetrifluoroacetate

(33a) Using a procedure analogous to reaction (3g),4-(aminomethyl)pyridine (3.61 g, 33 mmol) was treated withp-hydroxybenzoic acid (4.61 g, 1 eq) to yield the amide as a white solid(4.08 g, 54%).

(33b) Using a procedure analogous to reaction (1f), the amide (292 mg,1.28 mmol) from (33a) was reacted with4-(chloromethyl)-2-methylquinoline (245 mg, 1 eq) to yield the quinolineether (430 mg, 88%). MS Found: (M+H)⁺=384.

(33c) The quinoline ether (430 mg, 1.12 mmol) from (33b) was reactedwith Oxone (500 mg, 0.73 eq) and sodium bicarbonate (200 mg, 2.1 eq) inwater (1.7 mL) and methanol (5.5 mL) at 50° C. for 12 h. The reactionmixture was filtered, the filtrate was injected to reverse-phase HPLC toobtain the desired pyridine N-oxide (132.3 mg, 29%). MS Found:(M+H)⁺=400.

(33d) Using a procedure analogous to reaction (3h), dimethylmethylmalonate (5 mL, 37.57 mmol) was converted to 5-methylbarbituricacid (3.66 g, 69%).

(33e) The pyridine N-oxide (130 mg, 0.33 mmol) from (33c) and5-methylbarbituric acid (46 mg, 1 eq) from (33d) were dissolved inacetic anhydride (2 mL) and warmed to 80° C. for 19 h. The mixture wasconcentrated, dissolved in methanol and injected to reverse-phase HPLC.The title barbituric acid (54.8 mg, 32%) was obtained. MS Found:(M+H)⁺=524.

Example 344-(2-Methyl-quinolin-4-ylmethoxy)-N-[2,4,6-trioxo-5-(4-pyridin-3-ylmethyl-piperazin-1-yl)-hexahydro-pyrimidin-5-ylmethyl]-benzamide

Following the procedure analogous to that used in reaction (9), thecompound from Example 8 was reacted with 3-pyridine-carboxaldehyde for 2days to provide the title compound (7.6 mg, 51%). MS found:(M+H)⁺=608.4.

Example 35N-[5-(1-Methyl-piperidin-4-yl)-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide

Following procedure analogous to that used in reaction (9), the compoundfrom Example 29 was converted to the title compound (9 mg, 63%). MSfound: (M+H)⁺=530.4.

Example 36N-[5-(1-Isopropyl-piperidin-4-yl)-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide

Following the procedure analogous to that used in reaction (9), thecompound from Example 29 was reacted with acetone for 5 days to providethe title compound (7 mg, 32.8%). MS found: (M+H)⁺=558.4.

Example 374-(2-Methyl-quinolin-4-ylmethoxy)-N-[2,4,6-trioxo-5-(1-prop-2-ynyl-piperidin-4-yl)-hexahydro-pyrimidin-5-ylmethyl]-benzamide

Following the procedure analogous to that used in reaction (10), thecompound from Example 29 was reacted with propargyl bromide to providethe title compound (8.5 mg, 40%). MS found: (M+H)⁺=554.4.

Example 38N-[5-(1-Methanesulfonyl-piperidin-4-yl)-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide

Following the procedure analogous to that used in reaction (11), thecompound from Example 29 was converted to the title compound (5 mg,31%). MS found: (M+H)⁺=594.

Example 394-(2-Methyl-quinolin-4-ylmethoxy)-N-[2,4,6-trioxo-5-(1-pyridin-3-ylmethyl-piperidin-4-yl)-hexahydro-pyrimidin-5-ylmethyl]-benzamide

Following procedures analogous to that used in reaction (9), thecompound from Example 29 was reacted with 3-pyridinecarboxaldehyde for 2days to provide the title compound (7.3 mg, 45%). MS found:(M−H)⁻=605.5.

Example 404-(2-Methyl-quinolin-4-ylmethoxy)-N-{2,4,6-trioxo-5-[1-(tetrahydro-pyran-4-yl)-piperidin-4-yl]-hexahydro-pyrimidin-5-ylmethyl}-benzamide

Following the procedure analogous to that used in reaction (9), thecompound from Example 29 was reacted with tetrahydro-4H-pyran-4-one for5 days to provide the title compound (5 mg, 22%). MS found:(M+H)⁺=600.4.

Example 41N-[5-(1-Acetyl-piperidin-4-yl)-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide

Following the procedure analogous to that used in reaction (24), thecompound from Example 29 was converted to the title compound (5 mg,30%). MS found: (M+H)⁺=558.

Example 42N-{5-[1-(2,2-Dimethyl-propionyl)-piperidin-4-yl]-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl}-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide

Following the procedure analogous to that used in reaction (30), thecompound from Example 29 was converted to the title compound (14 mg,90%). MS found: (M+H)⁺=600.5.

Example 434-(2-Methyl-quinolin-4-ylmethoxy)-N-{2,4,6-trioxo-5-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-hexahydro-pyrimidin-5-ylmethyl}-benzamide

Following the procedure analogous to that used in reaction (25), thecompound from Example 29 was converted to the title compound (6 mg,48%). MS found: (M+H)⁺=621.4.

Example 444-[4-(2-Methyl-quinolin-4-ylmethoxy)-benzoylamino]-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]decane-2-carboxylicacid tert-butyl ester

(44a) To a −78° C. solution of N,N-diisopropylamine (5.87 mL, 41.8 mmol)in anhydrous THF (100 mL) was added n-butyllithium (1.6 M in hexane,26.0 mL, 41.6 mmol). After 30 min, a solution of3S,4S-4-benzyloxycarbonylamino-pyrrolidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester (synthesis described in WO0170673)(7.20 g, 19.0 mmol) in THF (50 mL) was cannulated into the above LDAsolution. The resulting mixture was stirred at −78° C. for 45 min.before methyl chloroformate (1.76 mL, 1.2 eq.) was added. The reactionwas continued to stir at −78° C. for 1 h, then quenched with aqueousammonium chloride (100 mL). The mixture was warmed to rt and extractedwith ethyl acetate (200 mL). The extract was washed with brine, dried(MgSO₄) and concentrated. Purification using silica gel chromatography(30%, then 40% ethyl acetate/hexane) provided the desired dimethyl ester(6.82 g). MS found: (M+Na)⁺=459.

(44b) The product from reaction 44a (3.40 g, 7.79 mmol) in methanol (80ml) was treated with 10 wt % palladium hydroxide on carbon (0.70 g) andstirred under balloon pressure hydrogen for 2 h. The mixture was purgedwith nitrogen and the catalyst removed by filtration. The filtrate wasconcentrated to provide the desired product (2.50 mg, 95%). MS found:(M+H)⁺=303.

(44c–d) Following procedures analogous to that used in reactions(12d–e), the title compound was obtained as a racemic material due toracemization that occurred during the barbituric acid formation (0.76 g,45% for 2 steps). MS found: (M+H)⁺=574.3; Chiral HPLC, for (44c), OJcolumn, methanol/isopropanol/hexane (1:1:8), 1.0 mL/min, ee % >99%; for(44d), AS column, methanol/isopropanol/hexane (7.5:7.5:85), 1.0 mL/min,ee % <6%.

Example 454-[4-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[1,4]thiazin-4-ylmethyl)-benzoylamino]-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]decane-2-carboxylicacid tert-butyl ester

(45a–b) Following the procedures analogous to that used in reaction44c–d, the intermediate from 44b was coupled with4-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[1,4]thiazin-4-ylmethyl)-benzoicacid, followed by barbituric acid formation to provide the titlecompound (0.24 g, 47% for 2 steps). MS found: (M+Na)⁺=620.1.

Example 464-[4-(2-Isopropyl-benzoimidazol-1-ylmethyl)-benzoylamino]-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]decane-2-carboxylicacid tert-butyl ester

(46a–b) Following the procedures analogous to that used in reactions44c–d, the intermediate from 44b was coupled with4-(2-isopropylbenzoimidazol-1-ylmethyl)benzoic acid, followed bybarbituric acid formation to provide the title compound (0.22 g, 60% for2 steps). MS found: (M+H)⁺=575.3.

Example 474-[4-(2-Methyl-quinolin-4-ylmethyl)-benzoylamino]-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]decane-2-carboxylicacid tert-butyl ester

(47a–b) Following the procedures analogous to that used in reactions44c–d, the intermediate from 44b was coupled with4-(2-methylquinolin-4-ylmethyl)benzoic acid, followed by barbituric acidformation to provide the title compound (0.11 g, 33% for 2 steps). MSfound: (M+H)⁺=558.3.

Example 484-(2-Methyl-quinolin-4-ylmethoxy)-N-(6,8,10-trioxo-2-oxa-7,9-diaza-spiro[4.5]dec-4-yl)-benzamide

(48a) Following the procedure analogous to that used in reaction 44a,4-[4-(2-Methyl-quinolin-4-ylmethoxy)-benzoylamino]-tetrahydro-furan-3-carboxylicacid methyl ester (0.20 g, 0.476 mmol) was converted to the desireddimethyl ester (48 mg, 21%). MS found: (M+H)⁺=479.3.

(48b) Following the procedure analogous to that used in reaction 44d,the dimethyl ester above was converted to the title compound (2 mg,4.5%). MS found: (M+H)⁺=475.3.

Example 497-[4-(2-Methyl-quinolin-4-ylmethoxy)-benzoylamino]-1,3,5-trioxo-2,4,9-triaza-spiro[5.5]undecane-9-carboxylicacid tert-butyl ester

(49a) Following the procedure analogous to that used in reaction 44a,3-[4-(2-Methyl-quinolin-4-ylmethoxy)-benzoylamino]-piperidine-1,4-dicarboxylicacid 1-tert-butyl ester 4-methyl ester (0.50 g, 0.914 mmol) wasconverted to the desired dimethyl ester (110 mg, 20%). MS found:(M+H)⁺=606.4.

(49b) Following the procedure analogous to that used in reaction 44d,the dimethyl ester above was converted to the title compound (27.6 mg,50.7%). MS found: (M+H)⁺=588.4.

Example 50N-(2-Acetyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide

Following the procedures analogous to that used in Examples 8 and 24,the compound from Example 44 was converted to the title compound (5 mg,22%). MS found: (M+H)⁺=516.

Example 51N-(2-Methanesulfonyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide

Following the procedures analogous to that used in Examples 8 and 11,the compound from Example 44 was converted to the title compound (7 mg,44%). MS found: (M+H)⁺=552.

Example 52N-[2-(2,2-Dimethyl-propionyl)-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide

Following the procedures analogous to that used in Examples 8 and 30,the compound from Example 44 was converted to the title compound (10 mg,63%). MS found: (M+H)⁺=558.

Example 534-(2-Methyl-quinolin-4-ylmethoxy)-N-[6,8,10-trioxo-2-(pyridine-3-carbonyl)-2,7,9-triaza-spiro[4.5]dec-4-yl]-benzamide

Following the procedures analogous to that used in Examples 8 and 25,the compound from Example 44 was converted to the title compound (20 mg,60%). MS found: (M+H)⁺=579.

Example 54N-(2-Acetyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-methyl-quinolin-4-ylmethyl)-benzamide

Following the procedures analogous to that used in Examples 8 and 24,the compound from Example 47 was converted to the title compound (5 mg,34%). MS found: (M+H)⁺=500.

Example 55N-(2-Methanesulfonyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-methyl-quinolin-4-ylmethyl)-benzamide

Following the procedures analogous to that used in Examples 8 and 11,the compound from Example 47 was converted to the title compound (11.9mg, 76.8%). MS found: (M+H)⁺=536.

Example 56N-(2-Acetyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(2-isopropyl-benzoimidazol-1-ylmethyl)-benzamide

Following the procedures analogous to that used in Examples 8 and 24,the compound from Example 46 was converted to the title compound (8 mg,54%). MS found: (M+H)⁺=517.

Example 574-(2-Isopropyl-benzoimidazol-1-ylmethyl)-N-(2-methanesulfonyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-benzamide

Following the procedures analogous to that used in Examples 8 and 11,the compound from Example 46 was converted to the title compound (13 mg,83%). MS found: (M+H)⁺=553.

Example 58N-(2-Acetyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-4-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[1,4]thiazin-4-ylmethyl)-benzamide

Following the procedures analogous to that used in Examples 8 and 24,the compound from Example 45 was converted to the title compound (8 mg,54%). MS found: (M+H)⁺=540.

Example 594-(1,-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[1,4]thiazin-4-ylmethyl)-N-(2-methanesulfonyl-6,8,10-trioxo-2,7,9-triaza-spiro[4.5]dec-4-yl)-benzamide

Following the procedures analogous to that used in Examples 8 and 11,the compound from Example 45 was converted to the title compound (3.6mg, 22%). MS found: (M+Na)⁺=598.

Example 60 1-(4-Phenoxy)phenyl-5,7-diazaspiro[2.5]octane-4,6,8-trione

(60a) A mixture of 4-hydroxybenzaldehyde (1.50 g, 12.3 mmol) anddiethylmalonate (2.52 g, 15.7 mmol), 0.12 mL of piperidine, and 0.06 mLof acetic acid were added to 6 mL of toluene. The reaction mixture washeated to reflux in a Dean-Stark apparatus for 18 h. The residue wasdiluted with methylene chloride, washed with 1N HCl, and saturatedsodium bicarbonate. The organic layer was separated, dried over sodiumsulfate, concentrated, and the residue purified by column chromatography(50% Ether/Hexanes), followed by trituration of the resulting solid withhexanes to provide diethyl-4-hydroxybenzylidenemalonate (60a) as a lightyellow solid. LCMS (M+H)⁺=256.35. ¹H NMR (CDCl₃) δ, 7.75, s, 1H, 7.40,d, 2H, 6.80, d, 2H, 5.90, s, 1H, 4.40–4.20, m, 4H, 1.25, t, 6H.

(60b) The product from (60a) (600 mg, 2.27 mmol), phenylboronic acid(571 mg, 4.54 mmol), copper (II) acetate (412 mg, 2.27 mmol) andpyridine (900 mg, 11.35 mmol) was suspended in 23 mL of methylenechloride at rt for 15 h. The mixture was filtered through Celite® andconcentrated. The residue was purified by silica gel chromatography (20%ether/hexanes) to provide 714 mg (92%) ofdiethyl-4-(Phenyloxy)benzylidenemalonate as a colorless oil. ¹H NMR(CDCl₃) δ, 7.75, s, 1H, 7.50–6.90, m, 9H, 4.40–4.20 m, 4H, 1.32, t, 6H.

(60c) A mixture of trimethylsulfoxonium chloride (308 mg, 2.35 mmol) andsodium hydride (60% in oil) (94 mg, 2.35 mmol) was stirred at roomtemperature for 20 min in 4 mL of DMSO. A solution ofdiethyl-4-(phenyloxy)benzylidenemalonate (714 mg, 2.09 mmol) in 4 mL ofTHF was added dropwise, and the reaction mixture stirred at rt for 1 h.The reaction mixture was then heated to 50° C. for 2 h and allowed tocool to rt. The mixture was poured into ice cold water, and extractedthree times with diethylether. The organic layer was washed with brine,separated, dried over magnesium sulfate and concentrated to provide2-(4-phenyloxy)phenyl-1,1-cyclopropanedicarboxylic acid diethyl ester inpurity >95% purity. ¹H NMR (CDCl₃) δ, 7.3–6.8, m, 9H, 4.40–4.20, m, 2H,3.95 q, 2H, 3.15, t, 1H, 3.15, m, 1H, 1.8, m, 1H, 1.3, t, 3H, 0.95, t,3H.

(60d) Sodium (66 mg, 2.86 mmol) was added to 10 mL of anhydrous ethanoland the mixture was stirred until homogeneous. Urea (215 mg, 3.57 mmol)was added and the mixture stirred at rt for 1 h. A solution of (60c) in10 mL of anhydrous ethanol was added dropwise and the mixture heated toreflux for 4 h. The mixture was cooled to rt, and partitioned beweenethyl acetate and water. The organic layer was washed with water andbrine, separated, dried over magnesium sulfate, and concentrated. Theresidue was purified by preparative HPLC to provide the title compoundin 5% yield. (M+MeOH—H)³¹ =354.3, (M−H)⁻=321.2. ¹H NMR (d₆-DMSO) δ,11.20, s, 1H, 11.10, s, 7.59–6.84 m, 9H, 3.65–3.60, m, 1H, 2.45–2.35 m,1H, 2.25–2.15, m, 1H.

Tables 1–4 below provide representative Examples, the synthesis of whichis described above, of the compounds of the present invention.

TABLE 1

MS [M + Ex R¹ W—U—X—Y U^(a)—X^(a)—Y^(a)—Z^(a) H] 1 Me —CH₂CO—(2-methyl-4- 446 quinolinyl)methoxy 2 Me —NHCO— (2-methyl-4- 447quinolinyl)methoxy 3 Me —NHCO— (1,1-dioxido-2,3- 471 dihydro-4H-1,4-benzothiazin-4- yl)methyl 4 Me —NHCO— (2-methyl-4- 431 quinolinyl)methyl5 Me —NHCO— (2-isopropyl-1H- 448 benzimidazol-1- yl)methyl 6 Me —CONH—(2-methyl-4- 447 quinolinyl)methoxy 7 4-Boc-1-piperazinyl —NHCO—(2-methyl-4- 617 quinolinyl)methoxy 8 1-piperazinyl —NHCO— (2-methyl-4-517 quinolinyl)methoxy 9 4-Me-1-piperazinyl —NHCO— (2-methyl-4- 531quinolinyl)methoxy 10 4-(2-propynyl)-1- —NHCO— (2-methyl-4- 555piperazinyl quinolinyl)methoxy 11 4-(methylsulfonyl)- —NHCO—(2-methyl-4- 595 1-piperazinyl quinolinyl)methoxy 12 NHBoc —NHCO—(2-methyl-4- 548 quinolinyl)methoxy 19 Et —NHCO— (2-methyl-4- 461quinolinyl)methoxy 20 4-benzyl-1- —NHCO— (2-methyl-4- 607.5 piperazinylquinolinyl)methoxy 21 isopropyl —NHCO— (2-methyl-4- 475quinolinyl)methoxy 23 4-isopropyl-1- —NHCO— (2-methyl-4- 559.6piperazinyl quinolinyl)methoxy 24 4-acetyl-1- —NHCO— (2-methyl-4- 559.5piperazinyl quinolinyl)methoxy 25 4-(3- —NHCO— (2-methyl-4- 622.5pyridinylcarbonyl)- quinolinyl)methoxy 1-piperazinyl 26 benzyl —NHCO—(2-methyl-4- 523 quinolinyl)methoxy 28 1-Boc-4-piperidinyl —NHCO—(2-methyl-4- 616.4 quinolinyl)methoxy 29 4-piperidinyl —NHCO—(2-methyl-4- 516.4 quinolinyl)methoxy 30 4-Piv-1-piperazinyl —NHCO—(2-methyl-4- 601.4 quinolinyl)methoxy 31 Me —NHCO— phenoxy [M − H] 36632 Me —NHCO— phenyl [M − H] 350 34 4-(3- —NHCO— (2-methyl-4- 608.4pyridinylmethyl)- quinolinyl)methoxy 1-piperazinyl 35 1-methyl-4- —NHCO—(2-methyl-4- 530.4 piperidinyl quinolinyl)methoxy 36 1-isopropyl-4-—NHCO— (2-methyl-4- 558.4 piperidinyl quinolinyl)methoxy 371-(2-propynyl)-4- —NHCO— (2-methyl-4- 554.4 piperidinylquinolinyl)methoxy 38 1-(methylsulfonyl)- —NHCO— (2-methyl-4- 5944-piperidinyl quinolinyl)methoxy 39 1-(3- —NHCO— (2-methyl-4- [M −pyridinylmethyl)- quinolinyl)methoxy H] 4-piperidinyl 605.5 401-(tetrahydro-pyran- —NHCO— (2-methyl-4- 600.4 4-yl)-4-piperidinylquinolinyl)methoxy 41 1-acetyl-4- —NHCO— (2-methyl-4- 558 piperidinylquinolinyl)methoxy 42 1-Piv-4-piperidinyl —NHCO— (2-methyl-4- 600.5quinolinyl)methoxy 43 1-(3- —NHCO— (2-methyl-4- 621.4pyridinylcarbonyl)- quinolinyl)methoxy 4-piperidinyl

TABLE 2

MS Ex A W—U—X—Y Z U^(a)—X^(a)—Y^(a) [M + H] 17 CH₂ —NHCO— 1,4-phenyleneOCH₂ 433 18 CH₂ —CONH— 1,4-phenylene OCH₂ 433 22 C(═O) —NHCO— 2,6- OCH₂497 naphthylene 27 C(═O) —NHCO— 1,3-phenylene — 417

TABLE 3

MS Ex q W—U—X—Y Z [M + H] 13 4 —NHCO— (2-methyl-4- 487quinolinyl)methoxy 14 3 —NHCO— (2-methyl-4- 473 quinolinyl)methoxy 60 1— phenoxy [M − H]   321.2

TABLE 3a

MS Ex q W—U—X—Y Z [M + H] 15* 1 —NHCO— (2-methyl-4- 473quinolinyl)methoxy 16* 1 —NHCO— (2-methyl-4- 473 quinolinyl)methoxy*stereoisomers

TABLE 3b

Example 44–47, 50–59

Example 48

Example 49 MS Ex R¹⁰ U^(a)—X^(a)—Y^(a)—Z^(a) [M + H] 44 Boc (2-methyl-4-574.3 quinolinyl)methoxy 45 Boc (1,1-dioxido-2,3-dihydro- [M + Na]4H-1,4-benzothiazin-4- 620.1 yl)methyl 46 Boc 2-isopropyl-1H- 575.3benzimidazol-1-yl)methyl 47 Boc (2-methyl-4- 558.3 quinolinyl)methyl 48— (2-methyl-4- 475.3 quinolinyl)methoxy 49 Boc (2-methyl-4- 588.4quinolinyl)methoxy 50 acetyl (2-methyl-4- 516 quinolinyl)methoxy 51methylsulfonyl 2-methyl-4- 552 quinolinyl)methoxy 52 Piv (2-methyl-4-558 quinolinyl)methoxy 53 3-pyridinylcarbonyl (2-methyl-4- 579quinolinyl)methoxy 54 acetyl (2-methyl-4- 500 quinolinyl)methyl 55methylsulfonyl (2-methyl-4- 536 quinolinyl)methyl 56 acetyl2-isopropyl-1H- 517 benzimidazol-1-yl)methyl 57 methylsulfonyl2-isopropyl-1H- 553 benzimidazol-1-yl)methyl 58 acetyl(1,1-dioxido-2,3-dihydro- 540 4H-1,4-benzothiazin-4- yl)methyl 59methylsulfonyl (1,1-dioxido-2,3-dihydro- 598 4H-1,4-benzothiazin-4-yl)methyl

TABLE 4

MS Ex R¹ R² U^(a)—X^(a)—Y^(a)—Z^(a) [M + H] 33 Me 4-pyridinyl(2-methyl-4- 524 quinolinyl)methoxy

The following tables contain additional representative examples of thepresent invention. Each entry in each table is intended to be pairedwith each formula at the start of the table. For example, example 1 inTable 5 is intended to be paired with each of the following formulaeA-AF.

TABLE 5

A B

C D

E F

G H

I J

K L

M N

O P

Q R n = 0–1

S T

U V

W X

Y Z

AA AB

AC AD

AE AF Ex R^(A) A 5-1 4-(2-trifluoromethylphenyl) benzoyl C(═O) 5-24-(2-trifluoromethylphenoxy) benzoyl C(═O) 5-34-(3-methyl-2-pyridinyl)benzoyl C(═O) 5-4 4-phenylbenzoyl C(═O) 5-54-phenoxybenzoyl C(═O) 5-6 4-benzyloxybenzoyl C(═O) 5-74-(2-methoxyphenyl)benzoyl C(═O) 5-8 4-(2-methylphenyl)benzoyl C(═O) 5-94-(2-methoxyphenoxy)benzoyl C(═O) 5-10 4-(2-methylphenoxy)benzoyl C(═O)5-11 4-(3-methylphenyl)benzoyl C(═O) 5-12 4-(4-quinolinyl)benzoyl C(═O)5-13 4-(3,5-dimethylphenyl)benzoyl C(═O) 5-14 2-[2-(2-methylphenyl)]pyridinylbenzoyl C(═O) 5-15 5-[2-(2-methoxyphenyl)] pyridinylcarbonylC(═O) 5-16 4-(2-methyl-4-quinolinylmethoxy)benzoyl C(═O) 5-174-[(2-methyl-4-quinolinyl)methyl]benzoyl C(═O) 5-184-(4-pyridinyl)benzoyl C(═O) 5-19 4-(2-butynyloxy)benzoyl C(═O) 5-204-(2-methylphenoxy)benzoyl C(═O) 5-214-(2-methyl-1-oxo-4-quinolinylmethoxy)benzoyl C(═O) 5-224-(2-methyl-1-oxo-4-quinolinylmethyl)benzoyl C(═O) 5-234-[(2-methyl-3-pyridinyl)methoxy]benzoyl C(═O) 5-244-[(2,5-dimethylbenzyl)oxy]benzoyl C(═O) 5-254-{[(2-methyl-4-quinolinyl)methyl]amino} benzoyl C(═O) 5-264-(3-phenyl-4,5-dihydro-5-isoxazolyl)benzoyl C(═O) 5-274-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]benzoyl 5-284-[3-(3-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]benzoyl 5-294-[3-(2-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]benzoyl 5-304-[3-(4-quinolinyl)-4,5-dihydro-5- C(═O) isoxazolyl]benzoyl 5-314-[3-(2,6-dimethyl-4-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]benzoyl5-32 3-methoxy-4-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O)isoxazolyl]benzoyl 5-33 4-[5-(4-pyridinyl)-4,5-dihydro-3- C(═O)isoxazolyl]benzoyl 5-34 4-[5-(3-pyridinyl)-4,5-dihydro-3- C(═O)isoxazolyl]benzoyl 5-35 4-[5-(2-pyridinyl)-4,5-dihydro-3- C(═O)isoxazolyl]benzoyl 5-36 1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-5-C(═O) carbonyl 5-37 6-[(2-methyl-4-quinolinyl)methoxy]-1-naphthoyl C(═O)5-38 6-[(2-methyl-4-quinolinyl)methyl]-1-naphthoyl C(═O) 5-396-[(2-methyl-4-quinolinyl)methoxy]-1,2,3,4- C(═O)tetrahydro-1-isoquinolinecarbonyl 5-406-[(2-methyl-4-quinolinyl)methyl]-1,2,3,4- C(═O)tetrahydro-1-isoquinolinecarbonyl 5-41{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl C(═O) 5-42{4-[(2-methyl-4-quinolinyl)methyl]phenyl}acetyl C(═O) 5-434-[(1H-benzimidazol-1-yl)methyl]benzoyl C(═O) 5-444-[(2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl C(═O) 5-454-[(2-isopropyl-1H-benzimidazol-1- C(═O) yl)methyl]benzoyl 5-464-(1H-indol-3-ylmethyl)benzoyl C(═O) 5-474-[(5-phenyl-1H-imidazol-1-yl)methyl]benzoyl C(═O) 5-484-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin- C(═O)4-yl)methyl]benzoyl 5-49 4-[2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-C(═O) benzothiazin-4-yl)methyl]benzoyl 5-504-(2-trifluoromethylphenyl)sulfonyl C(═O) 5-514-(2-trifluoromethylphenoxy)sulfonyl C(═O) 5-524-(3-methyl-2-pyridinyl)sulfonyl C(═O) 5-53 4-phenylsulfonyl C(═O) 5-544-phenoxysulfonyl C(═O) 5-55 4-benzyloxysulfonyl C(═O) 5-564-(2-methoxyphenyl)sulfonyl C(═O) 5-57 4-(2-methylphenyl)sulfonyl C(═O)5-58 4-(2-methoxyphenoxy)sulfonyl C(═O) 5-59 4-(2-methylphenoxy)sulfonylC(═O) 5-60 4-(3-methylphenyl)sulfonyl C(═O) 5-614-(4-quinolinyl)sulfonyl C(═O) 5-62 4-(3,5-dimethylphenyl)sulfonyl C(═O)5-63 5-[2-(2-methylphenyl)]pyridinylsulfonyl C(═O) 5-645-[2-(2-methoxyphenyl)]pyridinylsulfonyl C(═O) 5-654-(2-methyl-4-quinolinylmethoxy)sulfonyl C(═O) 5-664-(2-methyl-4-quinolinylmethyl)sulfonyl C(═O) 5-674-(4-pyridinyl)sulfonyl C(═O) 5-68 4-(2-butynyloxy)sulfonyl C(═O) 5-694-(2-methylphenoxy)sulfonyl C(═O) 5-704-(2-methyl-1-oxo-4-quinolinylmethoxy)sulfonyl C(═O) 5-714-(2-methyl-1-oxo-4-quinolinylmethyl)sulfonyl C(═O) 5-724-[(2-methyl-3-pyridinyl)methoxy]sulfonyl C(═O) 5-734-[(2,5-dimethylbenzyl)oxy]sulfonyl C(═O) 5-744-{[(2-methyl-4-quinolinyl)methyl]amino}sulfonyl C(═O) 5-754-(3-phenyl-4,5-dihydro-5-isoxazolyl)sulfonyl C(═O) 5-764-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]sulfonyl 5-774-[3-(3-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]sulfonyl 5-784-[3-(2-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]sulfonyl 5-794-[3-(4-quinolinyl)-4,5-dihydro-5- C(═O) isoxazolyl]sulfonyl 5-804-[3-(2,6-Dimethyl-4-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]sulfonyl5-81 3-methoxy-4-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O)isoxazolyl]sulfonyl 5-82 4-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O)isoxazolyl]sulfonyl 5-83 4-[5-(2-pyridinyl)-4,5-dihydro-3- C(═O)isoxazolyl]sulfonyl 5-84 4-[5-(4-pyridinyl)-4,5-dihydro-3- C(═O)isoxazolyl]sulfonyl 5-85 1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-5-C(═O) sulfonyl 5-86 1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-4- C(═O)sulfonyl 5-87 4-[(1H-benzimidazol-1-yl)methyl]sulfonyl C(═O) 5-884-[(2-methyl-1H-benzimidazol-1-yl)methyl]sulfonyl C(═O) 5-894-[(2-isopropyl-1H-benzimidazol-1- C(═O) yl)methyl]sulfonyl 5-904-(1H-indol-3-ylmethyl)sulfonyl C(═O) 5-914-[(5-phenyl-1H-imidazol-1-yl)methyl]sulfonyl C(═O) 5-924-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin- C(═O)4-yl)methyl]sulfonyl 5-934-[2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4- C(═O)benzothiazin-4-yl)methyl]sulfonyl 5-94 4-(4-quinolinyl)benzoyl CH₂ 5-954-(3,5-dimethylphenyl)benzoyl CH₂ 5-96 5-[2-(2-methylphenyl)]pyridinylbenzoyl CH₂ 5-97 5-[2-(2-methoxyphenyl)] pyridinylcarbonyl CH₂5-98 4-(2-methyl-4-quinolinylmethoxy)benzoyl CH₂ 5-994-(2-methyl-4-quinolinylmethyl)benzoyl CH₂ 5-1004-(2-methyl-1-oxo-4-quinolinylmethoxy)benzoyl CH₂ 5-1014-(2-methyl-1-oxo-4-quinolinylmethyl)benzoyl CH₂ 5-1024-[(2-methyl-3-pyridinyl)methoxy]benzoyl CH₂ 5-1034-[(2,5-dimethylbenzyl)oxy]benzoyl CH₂ 5-1044-{[(2-methyl-4-quinolinyl)methyl]amino}benzoyl CH₂ 5-1054-(3-phenyl-4,5-dihydro-5-isoxazolyl)benzoyl CH₂ 5-1064-[3-(4-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]benzoyl 5-1074-[3-(3-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]benzoyl 5-1084-[3-(2-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]benzoyl 5-1091-[(2-methyl-4-quinolinyl)methyl]-1H-indole-5- CH₂ carbonyl 5-1106-[(2-methyl-4-quinolinyl)methoxy]-1-naphthoyl CH₂ 5-1116-[(2-methyl-4-quinolinyl)methyl]-1-naphthoyl CH₂ 5-1126-[(2-methyl-4-quinolinyl)methoxy]-1,2,3,4- CH₂tetrahydro-1-isoquinolinecarbonyl 5-1136-[(2-methyl-4-quinolinyl)methyl]-1,2,3,4- CH₂tetrahydro-1-isoquinolinecarbonyl 5-1141-[(2-methyl-4-quinolinyl)methyl]-1H-indole-4- CH₂ carboxamide 5-115{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl CH₂ 5-116{4-[(2-methyl-4-quinolinyl)methyl]phenyl}acetyl CH₂ 5-1174-[(1H-benzimidazol-1-yl)methyl]benzoyl CH₂ 5-1184-[(2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl CH₂ 5-1194-[(2-isopropyl-1H-benzimidazol-1- CH₂ yl)methyl]benzoyl 5-1204-(1H-indol-3-ylmethyl)benzoyl CH₂ 5-1214-[(5-phenyl-1H-imidazol-1-yl)methyl]benzoyl CH₂ 5-1224-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin- CH₂ 4-yl)methyl]benzoyl5-123 4-[2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4- CH₂benzothiazin-4-yl)methyl]benzoyl

TABLE 6

AG AH

AI AJ

AK AL

AM AN

AO AP

AQ AR

AS AT

AU AV

AW AX n = 0–1

AY AZ

BA BB

BC BD

BE BF

BG BH

BI BJ

BK BL Ex R^(B) A 6-1 4-(2-trifluoromethylphenyl) anilino C(═O) 6-24-(2-trifluoromethylphenoxy) anilino C(═O) 6-34-(3-methyl-2-pyridinyl)anilino C(═O) 6-4 4-phenylanilino C(═O) 6-54-phenoxyanilino C(═O) 6-6 4-benzyloxyanilino C(═O) 6-74-(2-methoxyphenyl)anilino C(═O) 6-8 4-(2-methylphenyl)anilino C(═O) 6-94-(2-methoxyphenoxy)anilino C(═O) 6-10 4-(2-methylphenoxy)anilino C(═O)6-11 4-(3-methylphenyl)anilino C(═O) 6-12 4-(4-quinolinyl)anilino C(═O)6-13 4-(3,5-dimethylphenyl)anilino C(═O) 6-14 5-[2-(2-methylphenyl)]pyridinylanilino C(═O) 6-15 5-[2-(2-methoxyphenyl)] pyridyl amino C(═O)6-16 4-(2-methyl-4-quinolinylmethoxy)anilino C(═O) 6-174-(2-methyl-4-quinolinylmethyl)anilino C(═O) 6-18 4-(4-pyridinyl)anilinoC(═O) 6-19 4-(2-butynyloxy)anilino C(═O) 6-20 4-(2-methylphenoxy)anilinoC(═O) 6-21 4-(2-methyl-1-oxo-4-quinolinylmethoxy)anilino C(═O) 6-224-(2-methyl-1-oxo-4-quinolinylmethyl)anilino C(═O) 6-234-[(2-methyl-3-pyridinyl)methoxy]anilino C(═O) 6-254-[(2,5-dimethylbenzyl)oxy]anilino C(═O) 6-264-{[(2-methyl-4-quinolinyl)methyl]amino} C(═O) anilino 6-274-(3-phenyl-4,5-dihydro-5-isoxazolyl)anilino C(═O) 6-284-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]anilino 6-294-[3-(3-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]anilino 6-304-[3-(2-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]anilino 6-314-[3-(4-quinolinyl)-4,5-dihydro-5- C(═O) isoxazolyl]anilino 6-324-[3-(2,6-Dimethyl-4-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]anilino6-33 3-methoxy-4-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O)isoxazolyl]anilino 6-34 4-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O)isoxazolyl]anilino 6-35 4-[5-(2-pyridinyl)-4,5-dihydro-3- C(═O)isoxazolyl]anilino 6-36 4-[5-(4-pyridinyl)-4,5-dihydro-3- C(═O)isoxazolyl]anilino 6-37 1-[(2-methyl-4-quinolinyl)methyl]-1H-indolylC(═O) amino 6-38 6-[(2-methyl-4-quinolinyl)methoxy]-1- C(═O)naphthylamino 6-39 6-[(2-methyl-4-quinolinyl)methyl]-1- C(═O)naphthylamino 6-40 6-[(2-methyl-4-quinolinyl)methoxy]-1,2,3,4- C(═O)tetrahydro-1-isoquinolylamino 6-416-[(2-methyl-4-quinolinyl)methyl]-1,2,3,4- C(═O)tetrahydro-1-isoquinolylamino 6-42 1-[(2-methyl-4-quinolinyl)methyl]-1H-C(═O) benzimidazole-5-amino 6-431-[(2-methyl-4-quinolinyl)methyl]-1H-indole-4- C(═O) amino 6-44{4-[(2-methyl-4- C(═O) quinolinyl)methoxy]phenyl}benzyl 6-45{4-[(2-methyl-4- C(═O) quinolinyl)methyl]phenyl}benzyl 6-464-[(1H-benzimidazol-1-yl)methyl]anilino C(═O) 6-474-[(2-methyl-1H-benzimidazol-1- C(═O) yl)methyl]anilino 6-484-[(2-isopropyl-1H-benzimidazol-1- C(═O) yl)methyl]anilino 6-494-(1H-indol-3-ylmethyl)anilino C(═O) 6-504-[(5-phenyl-1H-imidazol-1-yl)methyl]anilino C(═O) 6-514-[(1,1-dioxido-2,3-dihydro-4H-1,4- C(═O)benzothiazin-4-yl)methyl]anilino 6-524-[2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H- C(═O)1,4-benzothiazin-4-yl)methyl]anilino 6-53 4-(2-trifluoromethylphenyl)anilino CH₂ 6-54 4-(2-trifluoromethylphenoxy) anilino CH₂ 6-554-(3-methyl-2-pyridinyl)anilino CH₂ 6-56 4-phenylanilino CH₂ 6-574-phenoxyanilino CH₂ 6-58 4-benzyloxyanilino CH₂ 6-594-(2-methoxyphenyl)anilino CH₂ 6-60 4-(2-methylphenyl)anilino CH₂ 6-614-(2-methoxyphenoxy)anilino CH₂ 6-62 4-(2-methylphenoxy)anilino CH₂ 6-634-(3-methylphenyl)anilino CH₂ 6-64 4-(4-quinolinyl)anilino CH₂ 6-654-(3,5-dimethylphenyl)anilino CH₂ 6-665-[2-(2-methylphenyl)]pyridinylanilino CH₂ 6-675-[2-(2-methoxyphenyl)]pyridyl amino CH₂ 6-684-(2-methyl-4-quinolinylmethoxy)anilino CH₂ 6-694-(2-methyl-4-quinolinylmethyl)anilino CH₂ 6-70 4-(4-pyridinyl)anilinoCH₂ 6-71 4-(2-butynyloxy)anilino CH₂ 6-72 4-(2-methylphenoxy)anilino CH₂6-73 4-(2-methyl-1-oxo-4-quinolinylmethoxy)anilino CH₂ 6-744-(2-methyl-1-oxo-4-quinolinylmethyl)anilino CH₂ 6-754-[(2-methyl-3-pyridinyl)methoxy]anilino CH₂ 6-764-[(2,5-dimethylbenzyl)oxy]anilino CH₂ 6-774-{[(2-methyl-4-quinolinyl)methyl]amino} CH₂ anilino 6-784-(3-phenyl-4,5-dihydro-5-isoxazolyl)anilino CH₂ 6-794-[3-(4-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino 6-804-[3-(3-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino 6-814-[3-(2-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino 6-824-[3-(4-quinolinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino 6-834-[3-(2,6-Dimethyl-4-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino6-84 3-methoxy-4-[3-(4-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino6-85 4-[3-(4-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino 6-864-[5-(2-pyridinyl)-4,5-dihydro-3- CH₂ isoxazolyl]anilino 6-874-[5-(4-pyridinyl)-4,5-dihydro-3- CH₂ isoxazolyl]anilino 6-881-[(2-methyl-4-quinolinyl)methyl]-1H-indolyl CH₂ amino 6-896-[(2-methyl-4-quinolinyl)methoxy]-1- CH₂ naphthylamino 6-906-[(2-methyl-4-quinolinyl)methyl]-1- CH₂ naphthylamino 6-916-[(2-methyl-4-quinolinyl)methoxy]-l,2,3,4- CH₂tetrahydro-1-isoquinolylamino 6-926-[(2-methyl-4-quinolinyl)methyl]-1,2,3,4- CH₂tetrahydro-1-isoquinolylamino 6-93 1-[(2-methyl-4-quinolinyl)methyl]-1H-CH₂ benzimidazole-5-amino 6-941-[(2-methyl-4-quinolinyl)methyl]-1H-indole-4- CH₂ amino 6-95{4-[(2-methyl-4- CH₂ quinolinyl)methoxy]phenyl}benzyl 6-96{4-[(2-methyl-4- CH₂ quinolinyl)methyl]phenyl}benzyl 6-974-[(1H-benzimidazol-1-yl)methyl]anilino CH₂ 6-984-[(2-methyl-1H-benzimidazol-1- CH₂ yl)methyl]anilino 6-994-[(2-isopropyl-1H-benzimidazol-1- CH₂ yl)methyl]anilino 6-1004-(1H-indol-3-ylmethyl)anilino CH₂ 6-1014-[(5-phenyl-1H-imidazol-1-yl)methyl]anilino CH₂ 6-1024-[(1,1-dioxido-2,3-dihydro-4H-1,4- CH₂ benzothiazin-4-yl)methyl]anilino6-103 4-[2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H- CH₂1,4-benzothiazin-4-yl)methyl]anilino

TABLE 7

BM BN

BO BP

BQ BR

BS BT

BU BV

BW BX

BY BZ

CA CB

CC CD n = 0–

CE CF

CG CH

CI CJ

CK CL

CM CN

CO CP

CQ CR Ex R^(C) A 7-1 4-(2-trifluoromethylphenyl) phenyl C(═O) 7-24-(2-trifluoromethylphenoxy) phenyl C(═O) 7-34-(3-methyl-2-pyridinyl)phenyl C(═O) 7-4 4-phenylphenyl C(═O) 7-54-phenoxyphenyl C(═O) 7-6 4-benzyloxyphenyl C(═O) 7-74-(2-methoxyphenyl)phenyl C(═O) 7-8 4-(2-methylphenyl)phenyl C(═O) 7-94-(2-methoxyphenoxy)phenyl C(═O) 7-10 4-(2-methylphenoxy)phenyl C(═O)7-11 4-(3-methylphenyl)phenyl C(═O) 7-12 4-(4-quinolinyl)phenyl C(═O)7-13 4-(3,5-dimethylphenyl)phenyl C(═O) 7-14 5-[2-(2-methylphenyl)]pyridinylphenyl C(═O) 7-15 5-[2-(2-methoxyphenyl)] pyridyl C(═O) 7-164-(2-methyl-4-quinolinylmethoxy)phenyl C(═O) 7-174-(2-methyl-4-quinolinylmethyl)phenyl C(═O) 7-18 4-(4-pyridinyl)phenylC(═O) 7-19 4-(-2-butynyloxy)phenyl C(═O) 7-20 4-(2-methylphenoxy)phenylC(═O) 7-21 4-(2-methyl-1-oxo-4-quinolinylmethoxy)phenyl C(═O) 7-224-(2-methyl-1-oxo-4-quinolinylmethyl)phenyl C(═O) 7-234-[(2-methyl-3-pyridinyl)methoxy]phenyl C(═O) 7-254-[(2,5-dimethylbenzyl)oxy]phenyl C(═O) 7-264-{[(2-methyl-4-quinolinyl)methyl]amino} C(═O) phenyl 7-274-(3-phenyl-4,5-dihydro-5-isoxazolyl)phenyl C(═O) 7-284-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]phenyl 7-294-[3-(3-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]phenyl 7-304-[3-(2-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]phenyl 7-314-[3-(4-quinolinyl)-4,5-dihydro-5- C(═O) isoxazolyl]phenyl 7-324-[3-(2,6-Dimethyl-4-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]phenyl7-33 3-methoxy-4-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]phenyl7-34 4-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]phenyl 7-354-[5-(2-pyridinyl)-4,5-dihydro-3- C(═O) isoxazolyl]phenyl 7-364-[5-(4-pyridinyl)-4,5-dihydro-3- C(═O) isoxazolyl]phenyl 7-371-[(2-methyl-4-quinolinyl)methyl]-1H-indolyl C(═O) amino 7-386-[(2-methyl-4-quinolinyl)methoxy]-1- C(═O) naphthylamino 7-396-[(2-methyl-4-quinolinyl)methyl]-1- C(═O) naphthylamino 7-406-[(2-methyl-4-quinolinyl)methoxy]-1,2,3,4- C(═O)tetrahydro-1-isoquinolyl 7-41 6-[(2-methyl-4-quinolinyl)methyl]-1,2,3,4-C(═O) tetrahydro-1-isoquinolyl 7-421-[(2-methyl-4-quinolinyl)methyl]-1H- C(═O) benzimidazole-5-amino 7-431-[(2-methyl-4-quinolinyl)methyl]-1H-indole-4- C(═O) amino 7-44{4-[(2-methyl-4- C(═O) quinolinyl)methoxy]phenyl}benzyl 7-45{4-[(2-methyl-4- C(═O) quinolinyl)methyl]phenyl}benzyl 7-464-[(1H-benzimidazol-1-yl)methyl]phenyl C(═O) 7-474-[(2-methyl-1H-benzimidazol-1- C(═O) yl)methyl]phenyl 7-484-[(2-isopropyl-1H-benzimidazol-1- C(═O) yl)methyl]phenyl 7-494-(1H-indol-3-ylmethyl)phenyl C(═O) 7-504-[(5-phenyl-1H-imidazol-1-yl)methyl]phenyl C(═O) 7-514-[(1,1-dioxido-2,3-dihydro-4H-1,4- C(═O)benzothiazin-4-yl)methyl]phenyl 7-524-[2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H- C(═O)1,4-benzothiazin-4-yl)methyl]phenyl 7-53 4-(2-trifluoromethylphenyl)phenyl CH₂ 7-54 4-(2-trifluoromethylphenoxy) phenyl CH₂ 7-554-(3-methyl-2-pyridinyl)phenyl CH₂ 7-56 4-phenylphenyl CH₂ 7-574-phenoxyphenyl CH₂ 7-58 4-benzyloxyphenyl CH₂ 7-594-(2-methoxyphenyl)phenyl CH₂ 7-60 4-(2-methylphenyl)phenyl CH₂ 7-614-(2-methoxyphenoxy)phenyl CH₂ 7-62 4-(2-methylphenoxy)phenyl CH₂ 7-634-(3-methylphenyl)phenyl CH₂ 7-64 4-(4-quinolinyl)phenyl CH₂ 7-654-(3,5-dimethylphenyl)phenyl CH₂ 7-66 5-[2-(2-methylphenyl)]pyridinylphenyl CH₂ 7-67 5-[2-(2-methoxyphenyl)] pyridyl CH₂ 7-684-(2-methyl-4-quinolinylmethoxy)phenyl CH₂ 7-694-(2-methyl-4-quinolinylmethyl)phenyl CH₂ 7-70 4-(4-pyridinyl)phenyl CH₂7-71 4-(2-butynyloxy)phenyl CH₂ 7-72 4-(2-methylphenoxy)phenyl CH₂ 7-734-(2-methyl-1-oxo-4-quinolinylmethoxy)phenyl CH₂ 7-744-(2-methyl-1-oxo-4-quinolinylmethyl)phenyl CH₂ 7-754-[(2-methyl-3-pyridinyl)methoxy]phenyl CH₂ 7-764-[(2,5-dimethylbenzyl)oxy]phenyl CH₂ 7-774-{[(2-methyl-4-quinolinyl)methyl]amino} CH₂ phenyl 7-784-(3-phenyl-4,5-dihydro-5-isoxazolyl)phenyl CH₂ 7-794-[3-(4-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]phenyl 7-804-[3-(3-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]phenyl 7-814-[3-(2-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]phenyl 7-824-[3-(4-quinolinyl)-4,5-dihydro-5- CH₂ isoxazolyl]phenyl 7-834-[3-(2,6-Dimethyl-4-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]phenyl7-84 3-methoxy-4-[3-(4-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]phenyl7-85 4-[3-(4-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]phenyl 7-864-[5-(2-pyridinyl)-4,5-dihydro-3- CH₂ isoxazolyl]phenyl 7-874-[5-(4-pyridinyl)-4,5-dihydro-3- CH₂ isoxazolyl]phenyl 7-881-[(2-methyl-4-quinolinyl)methyl]-1H-indolyl CH₂ amino 7-896-[(2-methyl-4-quinolinyl)methoxy]-1- CH₂ naphthylamino 7-906-[(2-methyl-4-quinolinyl)methyl]-1- CH₂ naphthylamino 7-916-[(2-methyl-4-quinolinyl)methoxy]-1,2,3,4- CH₂ tetrahydro-1-isoquinolyl7-92 6-[(2-methyl-4-quinolinyl)methyl]-1,2,3,4- CH₂tetrahydro-1-isoquinolyl 7-93 1-[(2-methyl-4-quinolinyl)methyl]-1H- CH₂benzimidazole-5-amino 7-941-[(2-methyl-4-quinolinyl)methyl]-1H-indole-4- CH₂ amino 7-95{4-[(2-methyl-4- CH₂ quinolinyl)methoxy]phenyl}benzyl 7-96{4-[(2-methyl-4- CH₂ quinolinyl)methyl]phenyl}benzyl 7-974-[(1H-benzimidazol-1-yl)methyl]phenyl CH₂ 7-984-[(2-methyl-1H-benzimidazol-1- CH₂ yl)methyl]phenyl 7-994-[(2-isopropyl-1H-benzimidazol-1- CH₂ yl)methyl]phenyl 7-1004-(1H-indol-3-ylmethyl)phenyl CH₂ 7-1014-[(5-phenyl-1H-imidazol-1-yl)methyl]phenyl CH₂ 7-1024-[(1,1-dioxido-2,3-dihydro-4H-1,4- CH₂ benzothiazin-4-yl)methyl]phenyl4-[2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H- CH₂1,4-benzothiazin-4-yl)methyl]phenyl 7-103 4-(2-trifluoromethylphenyl)anilino C(═O) 7-104 4-(2-trifluoromethylphenoxy) anilino C(═O) 7-1054-(3-methyl-2-pyridinyl)anilino C(═O) 7-106 4-phenylanilino C(═O) 7-1074-phenoxyanilino C(═O) 7-108 4-benzyloxyanilino C(═O) 7-1094-(2-methoxyphenyl)anilino C(═O) 7-10 4-(2-methylphenyl)anilino C(═O)7-111 4-(2-methoxyphenoxy)anilino C(═O) 7-112 4-(2-methylphenoxy)anilinoC(═O) 7-113 4-(3-methylphenyl)anilino C(═O) 7-1144-(4-quinolinyl)anilino C(═O) 7-115 4-(3,5-dimethylphenyl)anilino C(═O)7-116 5-[2-(2-methylphenyl)]pyridinylanilino C(═O) 7-1175-[2-(2-methoxyphenyl)]pyridyl amino C(═O) 7-1184-(2-methyl-4-quinolinylmethoxy)anilino C(═O) 7-1194-(2-methyl-4-quinolinylmethyl)anilino C(═O) 7-1204-(4-pyridinyl)anilino C(═O) 7-121 4-(2-butynyloxy)anilino C(═O) 7-1224-(2-methylphenoxy)anilino C(═O) 7-1234-(2-methyl-1-oxo-4-quinolinylmethoxy)anilino C(═O) 7-1254-(2-methyl-1-oxo-4-quinolinylmethyl)anilino C(═O) 7-1264-[(2-methyl-3-pyridinyl)methoxy]anilino C(═O) 7-1274-[(2,5-dimethylbenzyl)oxy]anilino C(═O) 7-1284-{[(2-methyl-4-quinolinyl)methyl]amino} C(═O) anilino 7-1294-(3-phenyl-4,5-dihydro-5-isoxazolyl)anilino C(═O) 7-1304-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]anilino 7-1314-[3-(3-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]anilino 7-1324-[3-(2-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]anilino 7-1334-[3-(4-quinolinyl)-4,5-dihydro-5- C(═O) isoxazolyl]anilino 7-1344-[3-(2,6-Dimethyl-4-pyridinyl)-4,5-dihydro-5- C(═O) isoxazolyl]anilino7-135 3-methoxy-4-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O)isoxazolyl]anilino 7-136 4-[3-(4-pyridinyl)-4,5-dihydro-5- C(═O)isoxazolyl]anilino 7-137 4-[5-(2-pyridinyl)-4,5-dihydro-3- C(═O)isoxazolyl]anilino 7-138 4-[5-(4-pyridinyl)-4,5-dihydro-3- C(═O)isoxazolyl]anilino 7-139 1-[(2-methyl-4-quinolinyl)methyl]-1H-indolylC(═O) amino 7-140 6-[(2-methyl-4-quinolinyl)methyl]-1- C(═O)naphthylamino 7-141 6-[(2-methyl-4-quinolinyl)methyl]-1,2,3,4- C(═O)tetrahydro-1-isoquinolylamino 7-1421-[(2-methyl-4-quinolinyl)methyl]-1H- C(═O) benzimidazole-5-amino 7-1431-[(2-methyl-4-quinolinyl)methyl]-1H-indole-4- C(═O amino 7-144{4-[(2-methyl-4- C(═O) quinolinyl)methoxy]phenyl}benzyl 7-145{4-[(2-methyl-4- C(═O) quinolinyl)methyl]phenyl}benzyl 7-1464-[(1H-benzimidazol-1-yl)methyl]anilino C(═O) 7-1474-[2-methyl-1H-benzimidazol-1- C(═O) yl)methyl]anilino 7-1484-[(2-isopropyl-1H-benzimidazol-1- C(═O) yl)methyl]anilino 7-1494-(1H-indol-3-ylmethyl)anilino C(═O) 7-1504-[(5-phenyl-1H-imidazol-1-yl)methyl]anilino C(═O) 7-1514-[(1,1-dioxido-2,3-dihydro-4H-1,4- C(═O)benzothiazin-4-yl)methyl]anilino 7-1524-[2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H- C(═O)1,4-benzothiazin-4-yl)methyl]anilino 7-153 4-(2-trifluoromethylphenyl)anilino CH₂ 7-154 4-(2-trifluoromethylphenoxy) anilino CH₂ 7-1554-(3-methyl-2-pyridinyl)anilino CH₂ 7-156 4-phenylanilino CH₂ 7-1574-phenoxyanilino CH₂ 7-158 4-benzyloxyanilino CH₂ 7-1594-(2-methoxyphenyl)anilino CH₂ 7-160 4-(2-methylphenyl)anilino CH₂ 7-1614-(2-methoxyphenoxy)anilino CH₂ 7-162 4-(2-methylphenoxy)anilino CH₂7-163 4-(3-methylphenyl)anilino CH₂ 7-164 4-(4-quinolinyl)anilino CH₂7-165 4-(3,5-dimethylphenyl)anilino CH₂ 7-166 5-[2-(2-methylphenyl)]pyridinylanilino CH₂ 7-167 5-[2-(2-methoxyphenyl)] pyridyl amino CH₂7-168 4-(2-methyl-4-quinolinylmethoxy)anilino CH₂ 7-1694-(2-methyl-4-quinolinylmethyl)anilino CH₂ 7-170 4-(4-pyridinyl)anilinoCH₂ 7-171 4-(2-butynyloxy)anilino CH₂ 7-172 4-(2-methylphenoxy)anilinoCH₂ 7-173 4-(2-methyl-1-oxo-4-quinolinylmethoxy)anilino CH₂ 7-1744-(2-methyl-1-oxo-4-quinolinylmethyl)anilino CH₂ 7-1754-[(2-methyl-3-pyridinyl)methoxy]anilino CH₂ 7-1764-[(2,5-dimethylbenzyl)oxy]anilino CH₂ 7-1774-{[(2-methyl-4-quinolinyl)methyl]amino} CH₂ anilino 7-1784-(3-phenyl-4,5-dihydro-5-isoxazolyl)anilino CH₂ 7-1794-[3-(4-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino 7-180}-4-[3-(3-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino 7-1814-[3-(2-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino 7-1824-[3-(4-quinolinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino 7-1834-[3-(2,6-Dimethyl-4-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino7-184 3-methoxy-4-[3-(4-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino7-185 4-[3-(4-pyridinyl)-4,5-dihydro-5- CH₂ isoxazolyl]anilino 7-1864-[5-(2-pyridinyl)-4,5-dihydro-3- CH₂ isoxazolyl]anilino 7-1874-[5-(4-pyridinyl)-4,5-dihydro-3- CH₂ isoxazolyl]anilino 7-1881-[(2-methyl-4-quinolinyl)methyl]-1H-indolyl CH₂ amino 7-1896-[(2-methyl-4-quinolinyl)methyl]-1- CH₂ naphthylamino 7-1906-[(2-methyl-4-quinolinyl)methyl]-1,2,3,4- CH₂tetrahydro-1-isoquinolylamino 7-1911-[(2-methyl-4-quinolinyl)methyl]-1H- CH₂ benzimidazole-5-amino 7-1921-[(2-methyl-4-quinolinyl)methyl]-1H-indole-4- CH₂ amino 7-193{4-[(2-methyl-4- CH₂ quinolinyl)methoxy]phenyl}benzyl 7-194{4-[(2-methyl-4- CH₂ quinolinyl)methyl]phenyl}benzyl 7-1954-[(1H-benzimidazol-1-yl)methyl]anilino CH₂ 7-1964-[(2-methyl-1H-benzimidazol-1- CH₂ yl)methyl]anilino 7-1974-[(2-isopropyl-1H-benzimidazol-1- CH₂ yl)methyl]anilino 7-1984-(1H-indol-3-ylmethyl)anilino CH₂ 7-1994-[(5-phenyl-1H-imidazol-1-yl)methyl]anilino CH₂ 7-2004-[(1,1-dioxido-2,3-dihydro-4H-1,4- CH₂ benzothiazin-4-yl)methyl]anilino7-201 4-[2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H- CH₂1,4-benzothiazin-4-yl)methyl]anilino

TABLE 8

CS

CT

CU

CV Ex R^(D) 8-1 (4-quinolinyl)methoxy 8-2 (4-quinolinyl)methyl 8-3(4-quinolinyloxy)methyl 8-4 (2-methyl-4-quinolinyloxy)methyl 8-5(2-chloro-4-quinolinyl)methoxy 8-6 (2-chloro-4-quinolinyl)methyl 8-7(2-chloro-4-quinolinyloxy)methyl 8-8 (2-isopropyl-4-quinolinyl)methoxy8-9 (2-isopropyl-4-quinolinyl)methyl 8-10(2-isopropyl-4-quinolinyloxy)methyl 8-11 (2-ethyl-4-quinolinyl)methoxy8-12 (2-ethyl-4-quinolinyl)methyl 8-13 (2-ethyl-4-quinolinyloxy)methyl8-14 (2-methoxy-4-quinolinyl)methoxy 8-15 (2-methoxy-4-quinolinyl)methyl8-16 (2-methoxy-4-quinolinyloxy)methyl 8-17(2-hydroxy-4-quinolinyl)methoxy 8-18 (2-hydroxy-4-quinolinyl)methyl 8-19(2-hydroxy-4-quinolinyloxy)methyl 8-20(2-trifluoromethyl-4-quinolinyl)methoxy 8-21(2-tritluoromethyl-4-quinolinyloxy)methyl 8-22(2-trifluoromethyl-4-quinolinyl)methyl 8-23(2-phenyl-4-quinolinyl)methoxy 8-24 (2-phenyl-4-quinolinyl)methyl 8-25(2-phenyl-4-quinolinyloxy)methyl 8-26 (2,3-dimethyl-4-quinolinyl)methoxy8-27 (2,3-dimethyl-4-quinolinyl)methyl 8-28(2,3-dimethyl-4-quinolinyloxy)methyl 8-29(2,6-dimethyl-4-quinolinyl)methoxy 8-30(2,6-dimethyl-4-quinolinyl)methyl 8-31(2,6-dimethyl-4-quinolinyloxy)methyl 8-32(2,7-dimethyl-4-quinolinyl)methoxy 8-33(2,7-dimethyl-4-quinolinyl)methyl 8-34(2,7-dimethyl-4-quinolinyloxy)methyl 8-35 (5-quinolinyl)methoxy 8-36(5-quinolinyl)methyl 8-37 (5-quinolinyloxy)methyl 8-38(7-methyl-5-quinolinyl)methoxy 8-39 (7-methyl-5-quinolinyl)methyl 8-40(7-methyl-5-quinolinyloxy)methyl 8-41 (7-methoxy-5-quinolinyl)methoxy8-42 (7-methoxy-5-quinolinyl)methyl 8-43(7-methoxy-5-quinolinyloxy)methyl 8-44 (8-quinolinyl)methoxy 8-45(8-quinolinyl)methyl 8-46 (8-quinolinyloxy)methyl 8-47(1-benzimidazolyl)methoxy 8-48 (1-benzimidazolyloxy)methyl 8-49(1-benzimidazolyl)methyl 8-50 1-(2-chloro-1-benzimidazolyl)methoxy 8-51[1-(2-chloro-benzimidazolyl)oxy]methyl 8-521-(2-chloro-benzimidazolyl)methyl 8-531-(2-methylthio-benzimidazolyl)methoxy 8-54[1-(2-methylthio-benzimidazolyl)oxy]methyl 8-551-(2-methylthio-benzimidazolyl)methyl 8-561-(2-methyl-benzimidazolyl)methoxy 8-57[1-(2-methyl-benzimidazolyl)oxy]methyl 8-581-(2-methyl-benzimidazolyl)methyl 8-591-(2-isopropyl-benzimidazolyl)methoxy 8-60[1-(2-isopropyl-benzimidazolyl)oxy]methyl 8-611-[2-(1,1-dimethylethyl)-benzimidazolyl]methoxy 8-62{1-[2-(1,1-dimethylethyl)-benzimidazolyl]oxy}methyl 8-631-[2-(1,1-dimethylethyl)-benzimidazolyl]methyl 8-641-(2-ethyl-benzimidazolyl)methoxy 8-65[1-(2-ethyl-benzimidazolyl)oxy]methyl 8-661-(2-ethyl-benzimidazolyl)methyl 8-671-(2-cyclopropyl-benzimidazolyl)methoxy 8-68[1-(2-cyclopropyl-benzimidazolyl)oxy]methyl 8-691-(2-cyclopropyl-benzimidazolyl)methyl 8-701-[2-(trifluoromethyl)-benzimidazolyl]methoxy 8-71{1-[2-(trifluoromethyl)-benzimidazolyl]oxy}methyl 8-721-[2-(trifluoromethyl)-benzimidazolyl]methyl 8-731-(2-phenyl-benzimidazolyl)methoxy 8-74[1-(2-phenyl-benzimidazolyl)oxy]methyl 8-751-(2-phenyl-benzimidazolyl)methyl 8-761-[2-(tert-butyl)-benzimidazolyl]methoxy 8-77{1-[2-(tert-butyl)-benzimidazolyl]oxy}methyl 8-781-[2-(tert-butyl)-benzimidazolyl]methyl 8-791-[2-(difluoromethyl)-benzimidazolyl]methoxy 8-80{1-[2-(difluoromethyl)-benzimidazolyl]oxy}methyl 8-811-[2-(difluoromethyl)-benzimidazolyl]methyl 8-821-[2-(fluoromethyl)-benzimidazolyl]methoxy 8-83{1-[2-(fluoromethyl)-benzimidazolyl}oxy}methyl 8-841-[2-(fluoromethyl)-benzimidazolyl]methyl 8-851-(2-cyclobutyl-benzimidazolyl)methoxy 8-86[1-(2-cyclobutyl-benzimidazolyl)oxy]methyl 8-871-(2-cyclobutyl-benzimidazolyl)methyl 8-881-[2-(1-methylcyclopropyl)-benzimidazolyl]methoxy 8-89{1-[2-(1-methylcyclopropyl)-benzimidazolyl]oxy]methyl 8-901-[2-(1-methylcyclopropyl)-benzimidazolyl]methyl 8-911-[2-(1-fluoro-1-methylethyl)-benzimidazolyl]methoxy 8-92{1-[2-(1-fluoro-1-methylethyl)- benzimidazolyl]oxy}methyl 8-931-[2-(1-fluoro-1-methylethyl)-benzimidazolyl]methyl 8-941-(2-methoxy-benzimidazolyl)methoxy 8-95[1-(2-methoxy-benzimidazolyl)oxy]methyl 8-961-(2-methoxy-benzimidazolyl)methyl 8-971-(1H-imidazo[4,5-b]pyridinyl)methoxy 8-98[1-(1H-imidazo[4,5-b]pyridinyl)oxy]methyl 8-99 1-(1H-imidazo[4,5-b]pyridinyl)methyl 8-1001-[2-methyl-(1H-imidazo[4,5-b]pyridinyl)]methoxy 8-101{1-[2-methyl-(1H-imidazo[4,5-b]pyridinyl)]oxy}methyl 8-1021-[2-methyl-(1H-imidazo[4,5-b]pyridinyl)]methyl 8-1031-(2-methyl-6-nitro-benzimidazolyl)methoxy 8-104[1-(2-methyl-6-nitro-benzimidazolyl)oxy]methyl 8-1051-(2-methyl-6-nitro-benzimidazolyl)methyl 8-1061-(2-methyl-5-chloro-benzimidazolyl)methoxy 8-107[1-(2-methyl-5-chloro-benzimidazolyl)oxy]methyl 8-1081-(2-methyl-5-chloro-benzimidazolyl)methyl 8-1091-(2-methyl-6-chloro-benzimidazolyl)methoxy 8-110[1-(2-methyl-6-chloro-benzimidazolyl)oxy]methyl 8-1111-(2-methyl-6-chloro-benzimidazolyl)methyl 8-1123-(2-methyl-1H-indolyl)methoxy 8-113 [3-(2-methyl-1H-indolyl)oxy]methyl8-114 3-(2-methyl-1H-indolyl)methyl 8-115 1-(2-methyl-1H-indolyl)methoxy8-116 [1-(2-methyl-1H-indolyl)oxy]methyl 8-1171-(2-methyl-1H-indolyl)methyl 8-118 3-(1,2-dimethyl-1H-indolyl)methoxy8-119 [3-(1,2-dimethyl-1H-indolyl)oxy]methyl 8-1203-(1,2-dimethyl-1H-indolyl)methyl 8-1211-(2,3-dimethyl-1H-indolyl)methoxy 8-122[1-(2,3-dimethyl-1H-indolyl)oxy]methyl 8-1231-(2,3-dimethyl-1H-indolyl)methyl 8-1241-(2-isopropyl-1H-indolyl)methoxy 8-125[1-(2-isopropyl-1H-indolyl)oxy]methyl 8-1261-(2-isopropyl-1H-indolyl)methyl 8-127 1-(2-isopropyl-1H-indolyl)methoxy8-128 [1-(2-isopropyl-1H-indolyl)oxy]methyl 8-1291-(2-isopropyl-1H-indolyl)methyl 8-130(2,3-dihydro-4H-1,4-benzothiazin-4-yl)methoxy 8-131[(2,3-dihydro-4H-1,4-benzothiazin-4-yl)oxy]methyl 8-132(2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl 8-133(1-oxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methoxy 8-134[(1-oxido-2,3-dihydro-4H-1,4-benzothiazin-4- yl)oxy]methyl 8-135(1-oxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl 8-136(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4- yl)methoxy 8-137(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4- yl)methyl 8-138(2,2-dimethyl-2,3-dihydro-4H-1,4-benzothiazin-4- yl)methoxy 8-139[(2,2-dimethyl-2,3-dihydro-4H-1,4-benzothiazin-4- yl)oxy]methyl 8-140(2,2-dimethyl-2,3-dihydro-4H-1,4-benzothiazin-4- yl)methyl 8-141(2,2-dimethyl-1-oxido-2,3-dihydro-4H-1,4-benzothiazin- 4-yl)methoxy8-142 [(2,2-dimethyl-1-oxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)oxy]methyl 8-143(2,2-dimethyl-1-oxido-2,3-dihydro-4H-1,4-benzothiazin- 4-yl)methyl 8-144(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4- benzothiazin-4-yl)methoxy8-145 [(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)oxy]methyl 8-146(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4- benzothiazin-4-yl)methyl8-147 (2,3-dihydro-4H-1,4-benzoxazin-yl)methoxy 8-148[(2,3-dihydro-4H-1,4-benzoxazin-yl)oxy]methyl 8-149(2,3-dihydro-4H-1,4-benzoxazin-yl)methyl 8-150(10H-phenoxazin-10-yl)methoxy 8-151 [(10H-phenoxazin-10-yl)oxy]methyl8-152 (10H-phenoxazin-10-yl)methyl

Utility

The compounds of formula I are expected to possess matrixmetalloprotease and/or aggrecanase and/or TNF-α inhibitory activity. TheMMP inhibitory activity of the compounds of the present invention isdemonstrated using assays of MMP activity, for example, using the assaydescribed below for assaying inhibitors of MMP activity. The compoundsof the present invention are expected to be bioavailable in vivo asdemonstrated, for example, using the ex vivo assay described below. Thecompounds of formula I are expected to have the ability tosuppress/inhibit cartilage degradation in vivo, for example, asdemonstrated using the animal model of acute cartilage degradationdescribed below.

The compounds provided by this invention should also be useful asstandards and reagents in determining the ability of a potentialpharmaceutical to inhibit MPs. These would be provided in commercialkits comprising a compound of this invention.

Metalloproteinases have also been implicated in the degradation ofbasement membranes to allow infiltration of cancer cells into thecirculation and subsequent penetration into other tissues leading totumor metastasis (Stetler-Stevenson, Cancer and Metastasis Reviews, 9,289–303, 1990). The compounds of the present invention should be usefulfor the prevention and treatment of invasive tumors by inhibition ofthis aspect of metastasis.

The compounds of the present invention should also have utility for theprevention and treatment of osteopenia associated with matrixmetalloprotease-mediated breakdown of cartilage and bone that occurs inosteoporosis patients.

Compounds that inhibit the production or action of TACE and/orAggrecanase and/or MMP's are potentially useful for the treatment orprophylaxis of various inflammatory, infectious, immunological ormalignant diseases or conditions. Thus, the present invention relates toa method of treating various inflammatory, infectious, immunological ormalignant diseases. These include acute infection, acute phase response,age related macular degeneration, alcoholic liver disease, allergy,allergic asthma, anorexia, aneurism, aortic aneurism, asthma,atherosclerosis, atopic dermatitis, autoimmune disease, autoimmunehepatitis, Bechet's disease, cachexia (including cachexia resulting fromcancer or HIV), calcium pyrophosphate dihydrate deposition disease,cardiovascular effects, chronic fatigue syndrome, chronic obstructionpulmonary disease, coagulation, congestive heart failure, cornealulceration, Crohn's disease, enteropathic arthropathy (includinginflammatory bowl disease), Felty's syndrome, fever, fibromyalgiasyndrome, fibrotic disease, gingivitis, glucocorticoid withdrawalsyndrome, gout, graft versus host disease, hemorrhage, HIV infection,hyperoxic alveolar injury, infectious arthritis, inflammation,intermittent hydrarthrosis, Lyme disease, meningitis, multiplesclerosis, myasthenia gravis, mycobacterial infection, neovascularglaucoma, osteoarthritis, pelvic inflammatory disease, periodontitis,polymyositis/dermatomyositis, post-ischaemic reperfusion injury,post-radiation asthenia, psoriasis, psoriatic arthritis, pulmonaryemphysema, pydoderma gangrenosum, relapsing polychondritis, Reiter'ssyndrome, rheumatic fever, rheumatoid arthritis (including juvenilerheumatoid arthritis and adult rheumatoid arthritis), sarcoidosis,scleroderma, sepsis syndrome, Still's disease, shock, Sjogren'ssyndrome, skin inflammatory diseases, solid tumor growth and tumorinvasion by secondary metastases, spondylitis, stroke, systemic lupuserythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener'sgranulomatosis.

Some compounds of the present invention have been shown to inhibit TNFproduction in lipopolysacharride stimulated mice, for example, using theassay for TNF induction in mice and in human whole blood as describedbelow.

Some compounds of the present invention have been shown to inhibitaggrecanase, a key enzyme in cartilage breakdown, as determined by theaggrecanase assay described below.

The compounds of the present invention can be administered alone or incombination with one or more additional anti-inflammatory agents. Theseagents include, but are not limited to, selective COX-2 inhibitors,interleukin-1 antagonists, dihydroorotate synthase inhibitors, p38 MAPkinase inhibitors, TNF-α inhibitors, and TNF-α sequestration agents.

By “administered in combination” or “combination therapy” it is meantthat a compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The term selective COX-2 inhibitors, as used herein, denotes agents thatselectively inhibit COX-2 function. Such agents include, but are notlimited to, celecoxib (Celebrex), rofecoxib (Vioxx), meloxicam(Movicox), etoricoxib, and valdecoxib.

TNF-α sequestration agents that may be used in combination with thecompounds of this invention, are TNF-α binding proteins or anti-TNF-αantibodies. These agents include, but are not limited to, etanercept(Enbrel) infliximab (Remicade), adalimumab (D2E7), CDP-571 (Humicade),and CDP-870.

Other anti-inflammatory agents that may be used in combination with thecompounds of this invention, include, but are not limited to,methotrexate, interleukin-1 antagonists (e.g., anakinra (Kineret)),dihydroorotate synthase inhibitors (e.g., leflunomide (Arava)), and p38MAP kinase inhibitors.

Administration of the compounds of the present invention in combinationwith such additional therapeutic agent, may afford an efficacy advantageover the compounds and-agents alone, and may do so while permitting theuse of lower doses of each. A lower dosage minimizes the potential ofside effects, thereby providing an increased margin of safety.

As used herein “μg” denotes microgram, “mg” denotes milligram, “g”denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L”denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM”denotes millimolar, “M” denotes molar and “nm” denotes nanometer. “Sigmastands for the Sigma-Aldrich Corp. of St. Louis, Mo.

A compound is considered to be active if it has an IC₅₀ or K_(i) valueof less than about 10 μM for the inhibition of a desired MP. Preferredcompounds of the present invention have K_(i)'s or IC₅₀'s of ≦1 μM. Morepreferred compounds of the present invention have K_(i)'s or IC₅₀'s of≦0.1 μM. Even more preferred compounds of the present invention haveK_(i)'s or IC₅₀'s of ≦0.01 μM. Still more preferred compounds of thepresent invention have K_(i)'s or IC₅₀'s of ≦0.001 μM.

Aggrecanase Enzymatic Assay

A novel enzymatic assay was developed to detect potential inhibitors ofaggrecanase. The assay uses active aggrecanase accumulated in media fromstimulated bovine nasal cartilage (BNC) or related cartilage sources andpurified cartilage aggrecan monomer or a fragment thereof as asubstrate.

The substrate concentration, amount of aggrecanases time of incubationand amount of product loaded for Western analysis were optimized for useof this assay in screening putative aggrecanase inhibitors. Aggrecanaseis generated by stimulation of cartilage slices with interleukin-1(IL-1), tumor necrosis factor alpha (TNF-α) or other stimuli. Matrixmetalloproteinases (MMPs) are secreted from cartilage in an inactive,zymogen form following stimulation, although active enzymes are presentwithin the matrix. We have shown that following depletion of theextracellular aggrecan matrix, active MMPs are released into the culturemedia (Tortorella, M. D. et al. Trans. Ortho. Res. Soc. 1995, 20, 341).Therefore, in order to accumulate BNC aggrecanase in culture media,cartilage is first depleted of endogenous aggrecan by stimulation with500 ng/ml human recombinant IL-β for 6 days with media changes every 2days. Cartilage is then stimulated for an additional 8 days withoutmedia change to allow accumulation of soluble, active aggrecanase in theculture media. In order to decrease the amount of other matrixmetalloproteinases released into the media during aggrecanaseaccumulation, agents which inhibit MMP-1, -2, -3, and -9 biosynthesisare included during stimulation. This BNC conditioned media, containingaggrecanase activity is then used as the source of aggrecanase for theassay. Aggrecanase enzymatic activity is detected by monitoringproduction of aggrecan fragments produced exclusively by cleavage at theGlu373-Ala374 bond within the aggrecan core protein by Western analysisusing the monoclonal antibody, BC-3 (Hughes, C E, et al., Biochem J306:799–804, 1995). This antibody recognizes aggrecan fragments with theN-terminus, 374ARGSVIL, generated upon cleavage by aggrecanase. The BC-3antibody recognizes this neoepitope only when it is at the N-terminusand not when it is present internally within aggrecan fragments orwithin the aggrecan protein core. Other proteases produced by cartilagein response to IL-1 do not cleave aggrecan at the Glu373-Ala374aggrecanase site; therefore, only products produced upon cleavage byaggrecanase are detected. Kinetic studies using this assay yield a Km of1.5+/−0.35 uM for aggrecanase.

To evaluate inhibition of aggrecanase, compounds are prepared as 10 mMstocks in DMSO, water or other solvents and diluted to appropriateconcentrations in water. Drug (50 ul) is added to 50 ul ofaggrecanase-containing media and 50 ul of 2 mg/ml aggrecan substrate andbrought to a final volume of 200 ul in 0.2 M Tris, pH 7.6, containing0.4 M NaCl and 40 mM CaCl₂. The assay is run for 4 hr at 37° C.,quenched with 20 mM EDTA and analyzed for aggrecanase-generatedproducts. A sample containing enzyme and substrate without drug isincluded as a positive control and enzyme incubated in the absence ofsubstrate serves as a measure of background.

Removal of the glycosaminoglycan side chains from aggrecan is necessaryfor the BC-3 antibody to recognize the ARGSVIL epitope on the coreprotein. Therefore, for analysis of aggrecan fragments generated bycleavage at the Glu373-Ala374 site, proteoglycans and proteoglycanfragments are enzymatically deglycosylated with chondroitinase ABC(0.1units/10 ug GAG) for 2 hr at 37° C. and then with keratanase (0.1units/10 ug GAG) and keratanase II (0.002 units/10 ug GAG) for 2 hr at37° C. in buffer containing 50 mM sodium acetate, 0.1 M Tris/HCl, pH6.5. After digestion, aggrecan in the samples is precipitated with 5volumes of acetone and resuspended in 30 ul of Tris glycine SDS samplebuffer (Novex) containing 2.5% beta mercaptoethanol. Samples are loadedand then separated by SDS-PAGE under reducing conditions with 4–12%gradient gels, transferred to nitrocellulose and immunolocated with1:500 dilution of antibody BC3. Subsequently, membranes are incubatedwith a 1:5000 dilution of goat anti-mouse IgG alkaline phosphatasesecond antibody and aggrecan catabolites visualized by incubation withappropriate substrate for 10–30 minutes to achieve optimal colordevelopment. Blots are quantitated by scanning densitometry andinhibition of aggrecanase determined by comparing the amount of productproduced in the presence versus absence of compound.

TNF PBMC Assay

Human peripheral blood mononuclear cells (PBMC) were obtained fromnormal donor blood by leukophoresis and isolated by Ficoll-Paque densityseparation. PBMCs were suspended in 0.05 ml RPMI 1640 with no serum at2×10⁶ cells/ml in 96 well polystyrene plates. Cells were preincubated 10minutes with compound, then stimulated with 1 μg/ml LPS(Lipopolysaccharide, Salmonella typhimurium) to induce TNF production.After an incubation of 5 hours at 37° C. in 95% air, 5% CO₂ environment,culture supernatants were removed and tested by standard sandwich ELISAfor TNF production.

TNF Human Whole Blood Assay

Blood is drawn from normal donors into tubes containing 143 USP units ofheparin/10 ml. 225 ul of blood is plated directly into sterilepolypropylene tubes. Compounds are diluted in DMSO/serum free media andadded to the blood samples so the final concentration of compounds are50, 10, 5, 1, 0.5, 0.1, and 0.01 μM. The final concentration of DMSOdoes not exceed 0.5%. Compounds are preincubated for 15 minutes beforethe addition of 100 ng/ml LPS. Plates are incubated for 5 hours in anatmosphere of 5% CO₂ in air. At the end of 5 hours, 750 ul of serum freemedia is added to each tube and the samples are spun at 1200 RPM for 10minutes. The supernatant is collected off the top and assayed forTNF-alpha production by a standard sandwich ELISA. The ability ofcompounds to inhibit TNF-alpha production by 50% compared to DMSOtreated cultures is given by the IC₅₀ value.

TNF Induction in Mice

Test compounds are administered to mice either I.P. or P.O. at timezero. Immediately following compound administration, mice receive anI.P. injection of 20 mg of D-galactosamine plus 10 μg oflipopolysaccharide. One hour later, animals are anesthetized and bled bycardiac puncture. Blood plasma is evaluated for TNF levels by an ELISAspecific for mouse TNF. Administration of representative compounds ofthe present invention to mice results in a dose-dependent suppression ofplasma TNF levels at one hour in the above assay.

MMP Assays

The enzymatic activities of recombinant MMP-1, 2, 3, 7, 8, 9, 10, 12,13, 14, 15, and 16 were measured at 25° C. with a fluorometric assay(Copeland, R. A. et al. Bioorganic Med. Chem. Lett. 1995, 5, 1947–1952).Final enzyme concentrations in the assay were between 0.05 and 10 nMdepending on the enzyme and the potency of the inhibitor tested. Thepermisive peptide substrate, MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH₂, waspresent at a final concentration of 10 uM in all assays. Initialvelocities, in the presence or absence of inhibitor, were measured asslopes of the linear portion of the product progress curves. IC50 valueswere determined by plotting the inhibitor concentration dependence ofthe fractional velocity for each enzyme, and fitting the data bynon-linear least squares methods to the standard isotherm equation(Copeland, R. A. Enzymes: A practical Introduction to Structure,Mechanism and Data Analysis, Wiley-VHC, New York, 1996, pp 187–223). Allof the compounds studied here were assumed to act as competitiveinhibitors of the enzyme, binding to the active site Zn atom aspreviously demonstrated by crystallographic studies of MMP-3 complexedwith related hydroxamic acids (Rockwell, A. et al. J. Am. Chem. Soc.1996, 118, 10337–10338). Based on the assumption of competitiveinhibiton, the IC50 values were converted to Ki values as previouslydescribed.

Compounds tested in the above assay are considered to be active if theyexhibit a K_(i) of ≦10 μM. Preferred compounds of the present inventionhave K_(i)'s of ≦1 μM. More preferred compounds of the present inventionhave K_(i)'s of ≦0.1 μM. Even more preferred compounds of the presentinvention have K_(i)'s of ≦0.01 μM. Still more preferred compounds ofthe present invention have K_(i)'s of ≦0.001 μM.

Using the methodology described above, a number of compounds of thepresent invention were found to exhibit K_(i)'s of ≦10 μM, therebyconfirming the utility of the compounds of the present invention.

Dosage and Formulation

The compounds of the present invention can be administered orally usingany pharmaceutically acceptable dosage form known in the art for suchadministration. The active ingredient can be supplied in solid dosageforms such as dry powders, granules, tablets or capsules, or in liquiddosage forms, such as syrups or aqueous suspensions. The activeingredient can be administered alone, but is generally administered witha pharmaceutical carrier. A valuable treatise with respect topharmaceutical dosage forms is Remington's Pharmaceutical Sciences, MackPublishing.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using dosageforms well known to those of ordinary skill in the pharmaceutical arts.An effective but non-toxic amount of the compound desired can beemployed as an antiinflammatory and antiarthritic agent.

The compounds of this invention can be administered by any means thatproduces contact of the active agent with the agent's site of action inthe body of a mammal. They can be administered by any conventional meansavailable for use in conjunction with pharmaceuticals, either asindividual therapeutic agents or in a combination of therapeutic agents.They can be administered alone, but generally administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient,and theeffect desired. An ordinarily skilled physician or veterinarian canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter, or arrest the progress of the condition.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. For a normal male adult human of approximately 70kg of body weight, this translates into a dosage of 70 to 1400 mg/day.Intravenously, the most preferred doses will range from about 1 to about10 mg/kg/minute during a constant rate infusion. Advantageously,compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three, or four times daily.

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wallknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittant throughout the dosageregimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients, orcarriers (collectively referred to herein as carrier materials) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups and the like, and consistentwith conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamallar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5–95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance. In general, water, a suitable oil, saline, aqueousdextrose (glucose), and related sugar solutions and glycols such aspropylene glycol or polyethylene glycols are suitable carriers forparenteral solutions. Solutions for parenteral administration preferablycontain a water soluble salt of the active ingredient, suitablestabilizing agents, and if necessary, buffer substances. Antioxidizingagents such as sodium bisulfite, sodium sulfite, or ascorbic acid,either alone or combined, are suitable stabilizing agents. Also used arecitric acid and its salts and sodium EDTA. In addition, parenteralsolutions can contain preservatives, such as benzalkonium chloride,methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

The compounds of the present invention may be administered incombination with a second therapeutic agent, especially non-steroidalanti-inflammatory drugs (NSAID's). The compound of Formula I and suchsecond therapeutic agent can be administered separately or as a physicalcombination in a single dosage unit, in any dosage form and by variousroutes of administration, as described above.

The compound of Formula I may be formulated together with the secondtherapeutic agent in a single dosage unit (that is, combined together inone capsule, tablet, powder, or liquid, etc.). When the compound ofFormula I and the second therapeutic agent are not formulated togetherin a single dosage unit, the compound of Formula I and the secondtherapeutic agent may be administered essentially at the same time, orin any order; for example the compound of Formula I may be administeredfirst, followed by administration of the second agent. When notadministered at the same time, preferably the administration of thecompound of Formula I and the second therapeutic agent occurs less thanabout one hour apart, more preferably less than about 5 to 30 minutesapart.

Preferably the route of administration of the compound of Formula I isoral. Although it is preferable that the compound of Formula I and thesecond therapeutic agent are both administered by the same route (thatis, for example, both orally), if desired, they may each be administeredby different routes and in different dosage forms (that is, for example,one component of the combination product may be administered orally, andanother component may be administered intravenously).

The dosage of the compound of Formula I when administered alone or incombination with a second therapeutic agent may vary depending uponvarious factors such as the pharmacodynamic characteristics of theparticular agent and its mode and route of administration, the age,health and weight of the recipient, the nature and extent of thesymptoms, the kind of concurrent treatment, the frequency of treatment,and the effect desired, as described above.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with asustained-release material which effects a sustained-release throughoutthe gastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of osteoarthritis or rheumatoidarthritis, which comprise one or more containers containing apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula I. Such kits may further include, if desired,one or more of various conventional pharmaceutical kit components, suchas, for example, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, mayalso be included in the kit.

In the present disclosure it should be understood that the specifiedmaterials and conditions are important in practicing the invention butthat unspecified materials and conditions are not excluded so long asthey do not prevent the benefits of the invention from being realized.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes, and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein; A is C(═O); B is O or S; L is O or S; W is selected from(CR^(a)R^(a1))_(m), C₂₋₃ alkenylene, and C₂₋₃ alkynylene; U is selectedfrom: C(O), CR^(a)(OH), C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O,OC(O)NR^(a1), NR^(a1)C(O)O, and NR^(a1)C(O)NR^(a1); X is absent or isselected from C₁₋₃ alkylene, C₂₋₃ alkenylene, and C₂₋₃ alkynylene; Y isabsent or is selected from O, NR^(a1), S(O)_(p), and C(O); Z is selectedfrom a C₃₋₁₃ carbocycle substituted with 0–5 R^(b), and a 5–14 memberedheterocycle comprising carbon atoms and 1–4 hetero atoms selected fromthe group consisting of N, O, and S(O)_(p), and substituted with 0–5R^(b); U^(a) is absent or is selected from: O, NR^(a1), C(O),CR^(a)(OH), C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O,OC(O)NR^(a1), NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p),S(O)_(p)NR^(a1), NR^(a1)S(O)_(p), and NR^(a1)SO₂NR^(a1); X^(a) is absentor is selected from C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀alkynylene; Y^(a) is absent or is selected from O, NR^(a1), S(O)_(p),and C(O); Z^(a) is selected from a C₃₋₁₃ carbocycle substituted with 0–5R^(c) and a 5–14 membered heterocycle comprising carbon atoms and 1–4hetero atoms selected from the group consisting of N, O, and S(O)_(p),and substituted with 0–5 R^(c); provided that U, Y, Z, U^(a), Y^(a), andZ^(a) do not combine to form a N—N, N—O, O—N, O—O, S(O)_(p)—O,O—S(O)_(p) or S(O)_(p)—S(O)_(p) group; R¹ is a 6 membered heterocyclecomprising carbon atoms and 1 nitrogen atom, and substituted with 0–5R^(d); R² is selected from Q¹, C₁₋₆ alkylene-Q¹, C₂₋₆ alkenylene-Q¹,C₂₋₆ alkynylene-Q¹, (CR^(a)R^(a1))_(r1)OR^(a1),(CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q^(a1),(CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q¹,(CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q¹,(CR^(a)R^(a1))_(r1)NR^(a)C(O)OR¹,(CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q¹,(CR^(a)R^(a1))_(r1)C(O)OR^(a1),(CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q¹,(CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q¹, and(CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1); R³ is selected from Q, C₁₋₆alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆ alkynylene-Q,(CR^(a)R^(a1))_(r1)OR^(a1),(CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)C(O)OR^(a1),(CR^(a)R^(a1))_(r1)OC(O)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)OC(O)OR^(a1), (CR^(a)R^(a1))_(r1)OC(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),(CR^(a)R^(a1))_(r1)NR^(a)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1),(CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q, and(CR^(a)R^(a1))_(r1)NR^(a)SO₂NR^(a)R^(a1); Q, at each occurrence, isindependently selected from H, CHF₂, CH₂F, CF₃, a C₃₋₁₃ carbocyclesubstituted with 0–5 R^(d), and a 5–14 membered heterocycle comprisingcarbon atoms and 1–4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p), and substituted with 0–5 R^(d); Q₁, at eachoccurrence, is independently selected from H, a C₃₋₁₃ carbocyclesubstituted with 0–5 R^(d), and a 5–14 membered heterocycle comprisingcarbon atoms and 1–4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p), and substituted with 0–5 R^(d); R⁴ is selected fromH, C₁₋₆ alkyl substituted with 0–1 R^(b), C₂₋₆ alkenyl substituted with0–1 R^(b), and C₂₋₆ alkynyl substituted with 0–1R^(b); R⁵ is selectedfrom H, C₁₋₆ alkyl substituted with 0–1R^(b), C₂₋₆ alkenyl substitutedwith 0–1 R^(b), and C₂₋₆ alkynyl substituted with 0–1 R^(b); n is 0 or1; alternatively, R² and R³, together with the carbon atom to which theyare attached, combine to form a 3–8 membered carbocyclic or heterocyclicring comprising carbon atoms, 0–2 ring heteroatoms selected from O, N,NR¹⁰, and S(O)_(p), and 0–2 double bonds, and substituted with 0–3R^(c); and the carbocyclic or heterocyclic ring is optionally fused to a5–6 membered carbocycle substituted with 0–3 R^(c) or a 5–6 memberedheterocycle consisting of carbon atoms and 1–3 heteroatoms selected fromthe group consisting of N, O, and S(O)_(p), and substituted with 0–3R^(c); alternatively, when n is 1, R² and R⁴, together with the carbonatoms to which they are attached, combine to form a 3–8 memberedcarbocyclic or heterocyclic ring comprising carbon atoms, 0–2 ringheteroatoms selected from O, N, NR¹⁰, and S(O)_(p), and 0–2 doublebonds, and substituted with 0–3 R^(c); and the carbocyclic orheterocyclic ring is optionally fused to a 5–6 membered carbocyclesubstituted with 0–3 R^(c) or a 5–6 membered heterocycle consisting ofcarbon atoms and 1–3 heteroatoms selected from the group consisting ofN, O, and S(O)_(p), and substituted with 0–3 R^(c); alternatively, whenn is 1, R⁴ and R⁵, together with the carbon atom to which they areattached, combine to form a 3–8 membered carbocyclic or heterocyclicring comprising carbon atoms, 0–2 ring heteroatoms selected from O, N,NR¹⁰, and S(O)_(p), and 0–2 double bonds, and substituted with 0–3R^(c); and the carbocyclic or heterocyclic ring is optionally fused to a5–6 membered carbocycle substituted with 0–3 R^(c) or a 5–6 memberedheterocycle consisting of carbon atoms and 1–3 heteroatoms selected fromthe group consisting of N, O, and S(O)_(p), and substituted with 0–3R^(c); R¹⁰, at each occurrence, is independently selected from H, C₁₋₆alkyl substituted with 0–2 R^(c1), C₂₋₆ alkenyl substituted with 0–2R^(c1), C₂₋₆ alkynyl substituted with 0–2 R^(c1),(CR^(a)R^(a1))_(s)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)OH,(CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),(CR^(a)R^(a1))_(r)C(S)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(s)NR^(a)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(S)NR^(a)R^(a1),(CR^(a)R^(a1))_(s)OC(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(s)NR^(a)C(O)OR^(a1),(CR^(a)R^(a1))_(s)NR^(a)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),(CR^(a)R^(a1))_(s)NR^(a)SO₂R^(a3),(CR^(a)R^(a1))_(s)NR^(a)SO₂NR^(a)R^(a1), (CR^(a)R^(a1))_(r)—C₃₋₁₀carbocycle substituted with 0–2 R^(c1), and (CR^(a)R^(a1))_(r)-5–14membered heterocycle consisting of carbon atoms and 1–4 heteroatomsselected from the group consisting of N, O, and S(O)_(p), andsubstituted with 0–2 R^(c1); R^(a1), at each occurrence, isindependently selected from H, C₁₋₆ alkyl, phenyl, and benzyl; R^(a1),at each occurrence, is independently selected from H, C_(1–6) alkylsubstituted with 0–1R^(e), C_(2–6) alkenyl substituted with 0–1 R^(e),C_(2–6) alkynyl substituted with 0–1R^(e), and —(CH₂)_(r)-3–8 memberedcarbocyclic or heterocyclic ring comprising carbon atoms and 0–2 ringheteroatoms selected from N, NR^(a2), O, and S(O)_(p), and substitutedwith 0–3 R^(e); alternatively, R^(a) and R^(a1), when attached to anitrogen, are taken together with the nitrogen to which they areattached, form a 5 or 6 membered heterocycle comprising carbon atoms and0–1 additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p);R^(a2), at each occurrence, is independently selected from C_(1–4)alkyl, phenyl, and benzyl; R^(a3), at each occurrence, is independentlyselected from H, C_(1–6) alkyl substituted with 0–1 R^(c1), C₂₋₆ alkenylsubstituted with 0–1 R^(c1), C₂₋₆ alkynyl substituted with 0–1R^(c1),and —(CH₂)_(r)-3–8 membered carbocyclic or heterocyclic ring comprisingcarbon atoms and 0–2 ring heteroatoms selected from N, NR^(a2), O, andS(O)_(p), and substituted with 0–3 R^(c1); R^(b), at each occurrence, isindependently selected from C_(1–6) alkyl substituted with 0–1R^(c1),OR^(a), SR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a),C(O)OR^(a), C(O)NR^(a)R^(a1), C(S)NR^(a)R^(a1), NR^(a)C(O)NR^(a)R^(a1),OC(O)NR^(a)R^(a1), NR^(a)C(O)OR^(a), S(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a3), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, CF₂CF₃, CHF₂, CH₂F, and phenyl;R^(c), at each occurrence, is independently selected from H, OR^(a), Cl,F, Br, I, ═O, —CN, NO₂, CF₃, CF₂CF₃, CH₂F, CHF₂,(CR^(a)R^(a1))_(r)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)C(═NCN)NR^(a)R^(a1),(CR^(a)R^(a1))_(r)C(═NR^(a))NR^(a)R^(a1),(CR^(a)R^(a1))_(r)C(═NOR^(a))NR^(a)R^(a1),(CR^(a)R^(a1))_(r1)C(O)NR^(a)OH, (CR^(a)R^(a1))_(r1)C(O)R^(a1),(CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(S)OR^(a1),(CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),(CR^(a)R^(a1))_(r)C(S)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)OC(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(r)NR^(a)C(O)OR^(a1),(CR^(a)R^(a1))_(r)NR^(a)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),(CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3),(CR^(a)R^(a1))_(r)NR^(a)SO₂NR^(a)R^(a1); C₁₋₆ alkyl substituted with 0–2R^(c1); C₂₋₆ alkenyl substituted with 0–2 R^(c1); C₂₋₆ alkynylsubstituted with 0–2 R^(c1); (CR^(a)R^(a1))_(r)—C₃₋₁₀ carbocyclesubstituted with 0–2 R^(c1); and (CR^(a)R^(a1))_(r)-5–14 memberedheterocycle comprising carbon atoms and 1–4 heteroatoms selected fromthe group consisting of N, O, and S(O)_(p), and substituted with 0–2R^(c1); alternatively, when two R^(c) groups are attached to the samecarbon atom, they form a spiro ring C that is a 3–11membered carbocycleor heterocycle substituted with 0–2 R^(c1) and comprising: carbon atoms,0–4 ring heteroatoms selected from O, N, and S(O)_(p), and 0–2 doublebonds, provided that ring C contains other than a S—S, O—O, or S—O bond;alternatively, when two R^(c) groups are attached to adjacent carbonatoms, together with the carbon atoms to which they are attached theyform a 5–7 membered carbocyclic or heterocyclic ring D substituted with0–2 R^(c1) and consisting of carbon atoms, 0–2 heteroatoms selected fromthe group consisting of N, O, and S(O)_(p), and 0–3 double bonds; R^(c1)at each occurrence, is independently selected from H, C₁₋₆ alkyl,OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2),NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2),S(O)_(p)R^(a2), CF₃, OCF₃, CF₂CF₃, CH₂F, CHF₂; R^(d), at eachoccurrence, is independently selected from C₁₋₆ alkyl substituted with0–2 R^(e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, I, ═O, —CN,NO₂, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a), C(O)NR^(a)R^(a1),C(S)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1),R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),S(O)_(p)R^(a3), CF₃, CF₂CF₃, (CH₂)_(r)—C₃₋₁₀ carbocycle substituted with0–2 R^(e), and a (CH₂)_(r)-5–14 membered heterocycle comprising carbonatoms and 1–4 heteroatoms selected from the group consisting of N, O,and S(O)_(p), and substituted with 0–2 R^(e). R^(e), at each occurrence,is independently selected from H, C₁₋₆ alkyl, OR^(a), Cl, F, Br, I, ═O,—CN, NO₂, NR^(a)R^(a), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a),R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a), R^(a)NC(O)OR^(a),S(O)₂NR^(a)R^(a), NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a),OS(O)₂NR^(a)R^(a), NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, OCF₃, CF₂CF₃,CH₂F, and CHF₂; m, at each occurrence, is selected from 0, 1, 2 and 3;p, at each occurrence, is selected from 0, 1, and 2; r, at eachoccurrence, is selected from 0, 1, 2, 3, and 4; r1, at each occurrence,is selected from 0, 1, 2, 3, and 4; and s, at each occurrence, isselected from 2, 3, and
 4. 2. A compound according to claim 1, wherein;W is (CHR^(a))m or C₂₋₃ alkenylene; U is selected from: C(O), C(O)O,OC(O), C(O)NR^(a1), and NR^(a1)C(O); X is absent or is C₁₋₃ alkylene;U^(a)is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH), C(O)O,C(O)NR^(a1), NR^(a1), C(O), S(O)_(p), S(O)_(p)NR^(a1), and NR^(a1),S(O)_(p); X^(a) is absent or is selected from C₁₋₄ alkylene, C₂₋₄alkenylene, and C₂₋₄ alkynylene; Y^(a) is absent or is selected from Oand NR^(a1); provided that U, Y, Z, U^(a), Y^(a) and Z^(a) do notcombine to form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) orS(O)_(p)—S(O)_(p) group; R² is selected from Q₁, C₁₋₆ alkylene-Q¹, C₂₋₆alkenylene-Q₁, C₂₋₆ alkynylene-Q¹, (CR^(a)R^(a1))_(r1)OR^(a1),(CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a))_(r)-Q¹,(CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q¹,(CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),(CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q¹,(CR^(a)R^(a1))_(r1)C(O)OR^(a1),(CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q¹, and(CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1); R³ is selected from Q, C₁₋₆alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆ alkynylene-Q,(CR^(a)R^(a1))_(r1)OR^(a1),(CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)C(O)OR^(a1),(CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),(CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1), and(CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q; Q, at each occurrence,is independently selected from H, CF₃, a C₃₋₁₃ carbocycle substitutedwith 0–5 R^(d), and a 5–14 membered heterocycle comprising carbon atomsand 1–4 heteroatoms selected from the group consisting of N, O, andS(O)_(p), and substituted with 0–5 R^(d); Q¹, at each occurrence, isindependently selected from H, a C₃₋₁₀ carbocycle substituted with 0–5R^(d), and a 5–10 membered heterocycle comprising carbon atoms and 1–4heteroatoms selected from the group consisting of N, O, and S(O)_(p),and substituted with 0–5 R^(d); R⁴ is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl; R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl; n is 0 or 1; alternatively, R² and R³,together with the carbon atom to which they are attached, combine toform a 3–8 membered carbocyclic or heterocyclic ring comprising carbonatoms, 0–2 ring heteroatoms selected from O, N, NR¹⁰, and S(O)_(p), and0–2 double bonds, and substituted with 0–2 R^(c); alternatively, when nis 1, R² and R⁴, together with the carbon atoms to which they areattached, combine to form a 3–8 membered carbocyclic or heterocyclicring comprising carbon atoms, 0–2 ring heteroatoms selected from O, N,NR¹⁰, and S(O)_(p), and 0–2 double bonds, and substituted with 0–2R^(c); alternatively, when n is 1, R⁴ and R⁵, together with the carbonatom to which they are attached, combine to form a 3–8 memberedcarbocyclic or heterocyclic ring comprising carbon atoms, 0–2 ringheteroatoms selected from O, N, NR¹⁰, and S(O)_(p), and 0–2 doublebonds, and substituted with 0–2 R^(c); R¹⁰, at each occurrence, isindependently selected from H, C₁₋₆ alkyl substituted with 0–2 R^(c1),C₂₋₆ alkenyl substituted with 0–2 R^(c1), C₂₋₆ alkynyl substituted with0–2 R^(c1), (CR^(a)R^(a1))_(s)NR^(a)R^(a1),(CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),(CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(s)NR^(a)C(O)R^(a1),(CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),(CR^(a)R^(a1))_(s)NR^(a)SO₂R^(a3), (CR^(a)R^(a1))_(r)—C₃₋₁₀ carbocyclesubstituted with 0–2 R_(c1), and (CR^(a)R^(a1))_(r)-5–14 memberedheterocycle consisting of carbon atoms and 1–4 heteroatoms selected fromthe group consisting of N, O, and S(O)_(p), and substituted with 0–2R^(c1); R^(c), at each occurrence, is independently selected from H,OR^(a), Cl, F, Br, ═O, —CN, NO₂, NR^(a)R^(a1)CF₃,(CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),(CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),(CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),(CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₁₋₆ alkyl substituted with 0–1R^(c1); C₂₋₆ alkenyl substituted with 0–1 R^(c1); C₂₋₆ alkynylsubstituted with 0–1 R^(c1); (CH₂)_(r)—C₃₋₆ carbocycle substituted with0–2 R^(c1); and (CH₂)_(r)-5–6 membered heterocycle comprising carbonatoms and 1–4 heteroatoms selected from the group consisting of N, O,and S(O)_(p), and substituted with 0–2 R^(c1); alternatively, when two Rgroups are attached to the same carbon atom, they form a spiro ring Cthat is a 3–8 membered carbocycle or heterocycle substituted with 0–2R^(c1) and comprising: carbon atoms, 0–4 ring heteroatoms selected fromO, N, and S(O)_(p), and 0–2 double bonds, provided that ring C containsother than a S—S, O—O, or S—O bond; and alternatively, when two R^(c)groups are attached to adjacent carbon atoms, together with the carbonatoms to which they are attached they form a 5–7 membered carbocyclic orheterocyclic ring D substituted with 0–2 R^(c1) and consisting of carbonatoms, 0–2 heteroatoms selected from the group consisting of N, O, andS(O)_(p), and 0–3 double bonds.
 3. A compound according to claim 2,wherein; A is C(═O); B is O; L is O; U is selected from: C(O),C(O)NR^(a1), and NR^(a1)C(O); X is absent, methylene or ethylene; Z isselected from: a C₃₋₈ cycloalkyl substituted with 0–5 R^(b); a C₃₋₈cycloalkenyl substituted with 0–5 R^(b); phenyl substituted with 0–5R^(b); naphthyl substituted with 0–5 R^(b); and a ^(5–14) memberedheterocycle comprising carbon atoms and 1–4 heteroatoms selected fromthe group consisting of N, O, and S(O)_(p), and substituted with 0–5R^(b); U^(a) is absent or is selected from: O, NR^(a1)C(O), C(O)NR^(a1),NR^(a1)C(O), and S(O)_(p); Z^(a) is selected from a C₅₋₁₀ carbocyclesubstituted with 0–5 R^(c), and a 5–14 membered heterocycle comprisingcarbon atoms and 1–4 hetero atoms selected from the group consisting ofN, O, and S(O)_(p), and substituted with 0–5 R^(c); provided that U, Y,Z, U^(a), Y^(a), and Z^(a) do not combine to form a N—N, N—O, O—N, O—O,S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group; R² is selected fromQ¹, C₁₋₆ alkylene-Q¹, C₂₋₆ alkenylene-Q¹, (CR^(a)R^(a1))_(r1)R^(a1),(CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q¹,(CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),(CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q¹,(CR^(a)R^(a1))_(r1)C(O)OR^(a1),(CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q¹, and(CR^(a)R^(a1))_(r1)S0 ₂NR^(a)R^(a1); Q¹, at each occurrence, isindependently selected from H, a C₃₋₆ carbocycle substituted with 0–3R^(d), and a 5–10 membered heterocycle comprising carbon atoms and 1–4heteroatoms selected from the group consisting of N, O, and S(O)_(p),and substituted with 0–3 R^(d); R³ is selected from Q, C₁₋₆ alkylene-Q,C₂₋₆ alkenylene-Q, C₂₋₆ alkynylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),(CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),(CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q, and(CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1); Q, at each occurrence, isindependently selected from H, a C₃₋₁₀ carbocycle substituted with 0–3R^(d), and a 5–14 membered heterocycle comprising carbon atoms and 1–4heteroatoms selected from the group consisting of N, O, and S(O)_(p),and substituted with 0–3 R^(d); R⁴ is selected from H and C₁₋₆ alkyl; R⁵is selected from H and C₁₋₆ alkyl; n is 0 or 1; R¹⁰, at each occurrence,is independently selected from H, C₁₋₆ alkyl substituted with 0–1 Rc¹,C₂₋₆ alkenyl substituted with 0–1 R^(c1), C₂₋₆ alkynyl substituted with0–1 R^(c1), (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),(CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3),(CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1), (CR^(a)R^(a1))_(r)—C₃₋₆carbocyclesubstituted with 0–2 R^(c1), and (CR^(a)R^(a1))_(r)-5–10 memberedheterocycle consisting of carbon atoms and 1–4 heteroatoms selected fromthe group consisting of N, O, and S(O)_(p), and substituted with 0–2R^(c1); R^(a), at each occurrence, is independently selected from H andC₁₋₆ alkyl; R^(a1), at each occurrence, is independently selected fromH, C₁₋₆ alkyl, phenyl, benzyl, 2-pyridinyl, 3 -pyridinyl, and4-pyridinyl; alternatively, R^(a) and R^(a1), when attached to anitrogen, are taken together with the nitrogen to which they areattached, form a 5 or 6 membered heterocycle comprising carbon atoms and0–1 additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p);R^(a3) at each occurrence, is independently selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, and —(CH₂)_(r)-3–8 membered carbocyclic or heterocyclicring comprising carbon atoms and 0–2 ring heteroatoms selected from N,NR^(a2), O, and S(O)_(p), and substituted with 0–3 R^(c1); R^(c), ateach occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a1), CF₃,(CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),(CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),(CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),(CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₃₋₆ carbocycle substituted with 0–2R^(c1); and 5–6 membered heterocycle comprising carbon atoms and 1–4heteroatoms selected from the group consisting of N, O, and S(O)_(p),and substituted with 0–2 R^(c1); alternatively, when two R^(c) groupsare attached to the same carbon atom, they form a spiro ring C that is a3–8 membered carbocycle or heterocycle substituted with 0–2 R^(c1) andcomprising: carbon atoms, 0–4 ring heteroatoms selected from O, N, andS(O)_(p), and 0–2 double bonds, provided that ring C contains other thana S—S, O—O, or S—O bond; alternatively, when two R groups are attachedto adjacent carbon atoms, together with the carbon atoms to which theyare attached they form a 5–6 membered carbocyclic or heterocyclic ring Dsubstituted with 0–2 R^(c1) and consisting of carbon atoms, 0–2heteroatoms selected from the group consisting of N, O, and S(O)_(p),and 0–3 double bonds; R^(c1), at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂,C(O)OR^(a), and C(O)NR^(a)R^(a1); R^(d), at each occurrence, isindependently selected from C₁₋₆ alkyl substituted with 0–2 R^(e), C₂₋₆alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O, —CN, NO₂, NR^(a)R^(a1),C(O)R^(a1), C(O)OR^(a), C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, (CH₂)_(r)—C ₃₋₆ carbocyclesubstituted with 0–2 R^(e), and a 5–6 membered heterocycle comprisingcarbon atoms and 1–4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p); and R_(e), at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂,C(O)OR^(a), and C(O)NR^(a)R^(a).
 4. A compound according to claim 3,wherein; W is (CH₂)_(m) or C₂₋₃ alkenylene; Z is selected from: a C₄₋₈cycloalkyl substituted with 0–3 R^(b); a C₄₋₈ cycloalkenyl substitutedwith 0–3 R^(b); phenyl substituted with 0–3 R^(b); naphthyl substitutedwith 0–3 R^(b); a 5–10 membered heterocycle substituted with 0–3 R^(b)and selected from the group: furanyl, tetrahydrofuranyl, thiazolyl,oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl,thiophenyl, triazinyl, pyridyl, pyrimidinyl, piperazinyl, piperidinyl,pyranyl, pyrazinyl, pyrazolyl, pyridoimidazole, pyrrolidinyl,pyrrolinyl, indolyl, indolinyl, benzimidazolyl, benzothiazinyl,benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl,tetrahydroquinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl,indazolyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, methylenedioxyphenyl, quinazolinyl, thiadiazinyl, and1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl; Z^(a)is selected from:phenyl substituted with 0–3 R^(c); naphthyl substituted with 0–3 R^(c);and a 5–10 membered heterocycle substituted with 0–3 R^(c) and selectedfrom the group: furanyl, tetrahydrofuranyl, thiazolyl, oxazolyl,imidazolyl, isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl,thiophenyl, triazinyl, pyridyl, pyrimidinyl, piperazinyl, piperidinyl,pyranyl, pyrazinyl, pyrazolyl, pyridoimidazole, pyrrolidinyl,pyrrolinyl, indolyl, indolinyl, benzimidazolyl, benzothiazinyl,benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl,tetrahydroquinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl,indazolyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, methylenedioxyphenyl, quinazolinyl, thiadiazinyl, and1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl; provided that U, Y, Z,U^(a), Y^(a), and Z^(a) do not combine to form a N—N, N—O, O—N, O—O,S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group; R³ is selected fromQ, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),(CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r),(CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),(CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q, and(CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1); Q, at each occurrence, isindependently selected from H, a C₃₋₆ carbocycle substituted with 0–3R^(d), and a 5–10 membered heterocycle comprising carbon atoms and 1–4heteroatoms selected from the group consisting of N, O, and S(O)_(p),and substituted with 0–3 R^(d); R^(a), at each occurrence, isindependently selected from H and C₁₋₆ alkyl; R^(a1), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, phenyl,benzyl, 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl; R^(a3), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, phenyl, andbenzyl; R^(b), at each occurrence, is independently selected from C₁₋₄alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a3), and CF₃; R^(c), ateach occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a1), CF₃,(CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),(CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),(CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),(CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₃₋₆ carbocycle substituted with 0–2R^(c1); and 5–6 membered heterocycle comprising carbon atoms and 1–4heteroatoms selected from the group consisting of N, O, and S(O)_(p),and substituted with 0–2 R^(c1); and R^(d), at each occurrence, isindependently selected from C₁₋₆ alkyl substituted with 0–1 R^(e), C₂₋₆alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a1), C(O)R^(a1),C(O)OR^(a), C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),S(O)_(p)R^(a3), CF₃, and (CH₂)_(r)-phenyl substituted with 0–2 R^(e). 5.A compound according to claim 4, wherein; X is absent or is methylene; Yis absent or is O; Z is selected from: phenyl substituted with 0–3R^(b); naphthyl substituted with 0–3 R^(b); thiophenyl substituted with0–2 Rb; oxazolyl substituted with 0–1 R^(b); isoxazolyl substituted with0–1 R^(b); and thiazolyl substituted with 0–1 R^(b); U^(a) is absent oris O; X^(a) is selected from CH₂ and CH₂CH₂; Y^(a)is absent or is O;Z^(a) is selected from: phenyl substituted with 0–3 R^(c); pyridylsubstituted with 0–3 R^(c); indolyl substituted with 0–3 R^(c);quinolinyl substituted with 0–3 R^(c); benzimidazolyl substituted with0–3 R^(c); and 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-ylsubstituted with 0–3 R^(c); provided that U, Y, Z, U^(a), Y^(a), andZ^(a) do not combine to form a N—N, N—O, O—N, O—O, S(O)_(p)—O,O—S(O)_(p) or S(O)_(p)—S(O)_(p) group; R¹ is a 6 membered heterocyclecomprising carbon atoms and 1 nitrogen atom, and substituted with 0–3R^(d); R² is selected from Q¹, C₁₋₆ alkylene-Q¹, C(O)NR^(a)R^(a1),C(O)(CR^(a)R^(a1))_(r)-Q¹, C(O)OR^(a1), andS(O)_(p)(CR^(a)R^(a1))_(r)-Q¹; Q¹, at each occurrence, is independentlyselected from H, a cyclopropyl substituted with 0–1 R^(d), cyclopentylsubstituted with 0–1 R^(d), cyclohexyl substituted with 0–1 R^(d),phenyl substituted with 0–2 R^(d), and a heteroaryl substituted with 0–3R^(d), wherein the heteroaryl is selected from pyridyl, quinolinyl,thiazolyl, furanyl, imidazolyl, and isoxazolyl; R³ is selected from Q,C₁₋₆ alkylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),(CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,(CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),(CR^(a)R^(a1))_(r1)S(O)(CR^(a)R^(a1))_(s)-Q, and(CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1); R⁴ is selected from H and C₁₋₄alkyl; R⁵ is selected from H and C₁₋₄ alkyl; and R^(c), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a1), CF₃,(CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),(CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3),(CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1)and phenyl.
 6. A compound according toclaim 5, wherein; R¹ is a heterocycle substituted with 0–3 R^(d),wherein the heterocycle is selected from pyridyl and piperindinyl; R³ isselected from Q, C₁₋₆ alkylene-Q, C(O)(CR^(a)R^(a1))_(r)-Q, C(O)OR^(a1),C(O)NR^(a)R^(a1), C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q, andS(O)_(p)(CR^(a)R^(a1))_(r)-Q; Q, at each occurrence, is independentlyselected from H, cyclopropyl substituted with 0–1 R^(d), cyclopentylsubstituted with 0–1 R^(d), cyclohexyl substituted with 0–1 R^(d),phenyl substituted with 0–2 R^(d), and a heteroaryl substituted with 0–3R^(d), wherein the heteroaryl is selected from pyridyl, quinolinyl,thiazolyl, furanyl, imidazolyl, and isoxazolyl; R⁴ is selected from H,methyl, and ethyl; R⁵ is selected from H, methyl, and ethyl; R^(c), ateach occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a1), CF₃,(CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),(CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), and(CR^(a)R^(a1))_(r)S(O)_(p)R^(a3); and r, at each occurrence, is selectedfrom 0, 1, 2, and
 3. 7. A compound according to claim 1, wherein thecompound is selected from the group: tert-butyl4-{5-[({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)methyl]-2,4,6-trioxohexahydro-5-pyrimidinyl}-1-piperidinecarboxylate;4-[(2-methyl-4-quinolinyl)methoxy]-N-{[2,4,6-trioxo-5-(4-piperidinyl)hexahydro-5-pyrimidinyl]methyl}benzmide;N-({5-[1-(2,2-dimethylpropanoyl)-4-piperidinyl]-2,4,6-trioxohexahydro-5-pyrimidinyl}methyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide;N-[5-(1-methyl-piperidin-4-yl)-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl]-4-(2-methyl-quinol4-ylmethoxy)-benzamide;N-[5-(1-isopropyl-piperidin-4-yl)-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;4-(2-methyl-quinolin-4-ylmethoxy)-N-[2,4,6-trioxo-5-(1-prop-2-ynyl-piperidin-4-yl)-hexahydro-pyrimidin-5-ylmethyl]-benzamide;N-[5-(1-methanesulfonyl-piperidin-4-yl)-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;4-(2-methyl-quinolin-4-ylmethoxy)-N-[2,4,6-trioxo-5-(1-pyridin-3-ylmethyl-piperidin-4-yl)-5-ylmethyl]-benzamide;4-(2-methyl-quinolin-4-ylmethoxy)-N-{2,4,6-trioxo-5-[1-(tetrahydro-pyran-4-yl)-piperidin-4-yl]-hexahydro-pyrimidin-5-ylmethyl}-benzamide;N-[5-(1-acetyl-piperidin-4-yl)-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl]-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;N-{5-[1-(2,2-dimethyl-propionyl)-piperidin-4-yl]-2,4,6-trioxo-hexahydro-pyrimidin-5-ylmethyl}-4-(2-methyl-quinolin-4-ylmethoxy)-benzamide;and4-(2-methyl-quinolin-4-ylmethoxy)-N-{2,4,6-trioxo-5-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-hexahydro-pyrimidin-5-ylmethyl}-benzamide;or a pharmaceutically acceptable salt form thereof.
 8. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt form thereof.
 9. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 2 or apharmaceutically acceptable salt form thereof.
 10. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 3 or apharmaceutically acceptable salt form thereof.
 11. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 4 or apharmaceutically acceptable salt form thereof.
 12. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 5 or apharmaceutically acceptable salt form thereof.
 13. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 6 or apharmaceutically acceptable salt form thereof.
 14. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 7 or apharmaceutically acceptable salt form thereof.